Co-administration of interleukin-3 mutant polypeptides with CSF&#39;s for multi-lineage hematopoietic cell production

ABSTRACT

The present invention relates to human interleukin-3 (hIL-3) variant or mutant proteins (muteins) functionally co-administered with other colony stimulating factors (CSF), cytokines, lymphokines, interleukins, hematopoietic growth factors or IL-3 variants.

This is a divisional of PCT/US95/01184 filed on Feb. 2, 1995 (and whichentered the U.S. National stage under 35 U.S.C. § 371 on Jun. 6, 1995 asSer. No. 08/466,871); which is a continuation-in-part of Ser. No.08/193,373, filed Feb. 4, 1994; which is a continuation-in-part ofinternational application PCT/US93/11197, filed on Nov. 22, 1993 (andwhich entered the U.S. national stage under 35 U.S.C. § 371 on Apr. 6,1995 as U.S. Ser. No. 08/411,795, now U.S. Pat. No. 5,604,116); which isa continuation-in-part of U.S. Ser. No. 07/981,044, filed Nov. 24, 1992,now abandoned.

FIELD OF THE INVENTION

The present invention relates to the coadministration or sequentialtreatment using mutants or variants of human interleukin-3 (hIL-3) andother colony stimulating factors (CSFs), cytokines, lymphokines,interleukins, hematopoietic growth factors or IL-3 variants.

BACKGROUND OF THE INVENTION

Colony stimulating factors (CSFs) which stimulate the differentiationand/or proliferation of bone marrow cells have generated much interestbecause of their therapeutic potential for restoring depressed levels ofhematopoietic stem cell-derived cells. CSFs in both human and murinesystems have been identified and distinguished according to theiractivities. For example, granulocyte-CSF (G-CSF) and macrophage-CSF(M-CSF) stimulate the in vitro formation of neutrophilic granulocyte andmacrophage colonies, respectively while GM-CSF and interleukin-3 (IL-3)have broader activities and stimulate the formation of both macrophage,neutrophilic and eosinophilic granulocyte colonies. IL-3 also stimulatesthe formation of mast, megakaryocyte and pure and mixed erythroidcolonies (when erythropoietin is added).

Because of its ability to stimulate the proliferation of a number ofdifferent cell types and to support the growth and proliferation ofprogenitor cells, IL-3 has potential for therapeutic use in restoringhematopoietic cells to normal amounts in those cases where the number ofcells has been reduced due to diseases or to therapeutic treatments suchas radiation and/or chemotherapy.

Interleukin-3 (IL-3) is a hematopoietic growth factor which has theproperty of being able to promote the survival, growth anddifferentiation of hematopoietic cells. Among the biological propertiesof IL-3 are the ability (a) to support the growth and differentiation ofprogenitor cells committed to all, or virtually all, blood celllineages; (b) to interact with early multipotential stem cells; (c) tosustain the growth of pluripotent precursor cells; (d) to stimulateproliferation of chronic myelogenous leukemia (CML) cells; (e) tostimulate proliferation of mast cells, eosinophils and basophils; (f) tostimulate DNA synthesis by human acute myelogenous leukemia (AML) cells;(g) to prime cells for production of leukotrienes and histamines; (h) toinduce leukocyte chemotaxis; and (i) to induce cell surface moleculesneeded for leukocyte adhesion.

Mature human interleukin-3 (hIL-3) consists of 133 amino acids. It hasone disulfide bridge and two potential glycosylation sites (Yang, etal., CELL 47:3 (1986)).

Murine IL-3 (mIL-3) was first identified by Ihle, et al., J. IMMUNOL.126:2184 (1981) as a factor which induced expression of a T cellassociated enzyme, 20-hydroxysteroid dehydrogenase. The factor waspurified to homogeneity and shown to regulate the growth anddifferentiation of numerous subclasses of early hematopoietic andlymphoid progenitor cells.

In 1984, cDNA clones coding for murine IL-3 were isolated (Fung, et al.,NATURE 307:233 (1984) and Yokota, et al., PROC. NATL. ACAD. SCI. USA81:1070 (1984)). The murine DNA sequence coded for a polypeptide of 166amino acids including a putative signal peptide.

The gibbon IL-3 sequence was obtained using a gibbon cDNA expressionlibrary. The gibbon IL-3 sequence was then used as a probe against ahuman genomic library to obtain a human IL-3 sequence.

Gibbon and human genomic DNA homologues of the murine IL-3 sequence weredisclosed by Yang, et al., CELL 47:3 (1986). The human sequence reportedby Yang, et al. included a serine residue at position 8 of the matureprotein sequence. Following this finding, others reported isolation ofPro⁸ hIL-3 cDNAs having proline at position 8 of the protein sequence.Thus it appears that there may be two allelic forms of hIL-3.

Dorssers, et al., GENE 55:115 (1987), found a clone from a human cDNAlibrary which hybridized with mIL-3. This hybridization was the resultof the high degree of homology between the 3' noncoding regions of mIL-3and hIL-3. This cDNA coded for an hIL-3 (Pro⁸) sequence.

U.S. Pat. No. 4,877,729 and U.S. Pat. No. 4,959,454 disclose human IL-3and gibbon IL-3 cDNAs and the protein sequences for which they code. ThehIL-3 disclosed has serine rather than proline at position 8 in theprotein sequence.

Clark-Lewis, et al., SCIENCE 231:134 (1986) performed a functionalanalysis of murine IL-3 analogs synthesized with an automated peptidesynthesizer. The authors concluded that the stable tertiary structure ofthe complete molecule was required for full activity. A study on therole of the disulfide bridges showed that replacement of all fourcysteines by alanine gave a molecule with 1/500th the activity as thenative molecule. Replacement of two of the four Cys residues byAla(Cys⁷⁹, Cys¹⁴⁰ →Ala⁷⁹, Ala¹⁴⁰) resulted in an increased activity. Theauthors concluded that in murine IL-3 a single disulfide bridge isrequired between cysteines 17 and 80 to get biological activity thatapproximates physiological levels and that this structure probablystabilizes the tertiary structure of the protein to give a conformationthat is optimal for function. (Clark-Lewis, et al., PROC. NATL. ACAD.SCI. USA 85:7897 (1988)).

International Patent Application (PCT) WO 88/00598 discloses gibbon- andhuman-like IL-3. The hIL-3 contains a Ser⁸ →Pro⁸ replacement.Suggestions are made to replace Cys by Ser, thereby breaking thedisulfide bridge, and to replace one or more amino acids at theglycosylation sites.

EP-A-0275598 (WO 88/04691) illustrates that Ala¹ can be deleted whileretaining biological activity. Some mutant hIL-3 sequences are provided,e.g., two double mutants, Ala¹ →Asp¹, Trp¹³ →Arg¹³ (pGB/IL-302) and Ala¹→Asp¹, Met³ →Thr³ (pGB/IL-304) and one triple mutant Ala¹ →Asp¹, Leu⁹→Pro⁹, Trp¹³ →Arg¹³ (pGB/IL-303).

WO 88/05469 describes how deglycosylation mutants can be obtained andsuggests mutants of Arg⁵⁴ Arg⁵⁵ and Arg¹⁰⁸ Arg¹⁰⁹ Lys¹¹⁰ might avoidproteolysis upon expression in Saccharomyces cerevisiae by KEX2protease. No mutated proteins are disclosed. Glycosylation and the KEX2protease activity are only important, in this context, upon expressionin yeast.

WO 88/06161 mentions various mutants which theoretically may beconformationally and antigenically neutral. The only actually performedmutations are Met² →Ile² and Ile¹³¹ →Leu¹³¹. It is not disclosed whetherthe contemplated neutralities were obtained for these two mutations.

WO 91/00350 discloses nonglycosylated hIL-3 analog proteins, forexample, hIL-3 (Pro⁸ Asp¹⁵ Asp⁷⁰), Met³ rhuIL-3 (Pro⁸ Asp¹⁵ Asp⁷⁰); Thr⁴rhuIL-3 (Pro⁸ Asp¹⁵ Asp⁷⁰)and Thr⁶ rhuIL-3 (Pro⁸ Asp¹⁵ Asp⁷⁰). It issaid that these protein compositions do not exhibit certain adverse sideeffects associated with native hIL-3 such as urticaria resulting frominfiltration of mast cells and lymphocytes into the dermis. Thedisclosed analog hIL-3 proteins may have N termini at Met³, Thr⁴, orThr⁶.

WO 91/12874 discloses cysteine added variants (CAVs) of IL-3 which haveat least one Cys residue substituted for a naturally occurring aminoacid residue.

U.S. Pat. No. 4,810,643 discloses the DNA sequence encoding human G-CSF.

WO 91/07988 discloses a method to increase megakaryocyte productioncomprised of administration of G-CSF with IL-3 or GM-CSF. Also disclosedis a method for increasing platelet production comprised ofadministration of IL-6 with IL-3, G-CSF or GM-CSF.

SUMMARY OF THE INVENTION

The present invention encompasses recombinant human interleukin-3(hIL-3) variant or mutant proteins (muteins) These hIL-3 muteins containamino acid substitutions and may also have amino acid deletions ateither/or both the N- and C-termini. This invention encompassescoadministration or sequential treatment using IL-3 variants of thepresent invention with other colony stimulating factors (CSFs),cytokines, lymphokines, interleukins, hematopoietic growth factors(herein after collectively referred to as "colony stimulating factors")which may have the potential for therapeutic use in restoringhematopoietic cells to normal amounts in those cases where the number ofcells has been reduced due to diseases or to therapeutic treatments suchas radiation and/or chemotherapy. Coadministration or sequentialtreatment using IL-3 variants of the present invention with other colonystimulating factors may enhance therapeutic value due to the synergisticeffects of the proteins that make up the treatment. The use of multiplefactors may also have the potential advantage by lowering the demandsplaced on factor-producing cells and their induction systems. If thereare limitations in the ability of a cell to produce a factor then bylowering the required concentrations of each of the factors by usingthem in combination may usefully reduce demands on the factor-producingcells. The use of multiple factors may lower the amount of the factorsthat would be needed, probably reducing the likelihood of adverseresponses.

Coadministration or sequential treatment may have the usual activity ofthe peptides forming the mixture or it may be further characterized byhaving a biological or physiological activity greater than simply theadditive function of the presence of IL-3 or the other growth factorsalone. Coadministration or sequential treatment may also unexpectedlyprovide an enhanced effect on the activity or an activity different fromthat expected by the presence of IL-3 or the other growth factors. TheIL-3 variants of the present invention may also have an improvedactivity profile which may include reduction of undesirable biologicalactivities associated with native hIL-3.

The present invention includes mutants of hIL-3 in which from 1 to 14amino acids have been deleted from the N-terminus and/or from 1 to 15amino acids have been deleted from the C-terminus, containing multipleamino acid substitutions, which are used with other growth factors orIL-3 variant. Preferred IL-3 variants of the present invention includevariants in which amino acids 1 to 14 have been deleted from theN-terminus, amino acids 126 to 133 have been deleted from the C-terminusand contain from about four to about twenty-six amino acid substitutionsin the polypeptide sequence.

The present invention also provides IL-3 variants which may function asIL-3 antagonists or as discrete antigenic fragments for the productionof antibodies useful in immunoassay and immunotherapy protocols.Antagonists of hIL-3 would be particularly useful in blocking the growthof certain cancer cells like AML, CML and certain types of B lymphoidcancers. Other conditions where antagonists would be useful includethose in which certain blood cells are produced at abnormally highnumbers or are being activated by endogenous ligands. Antagonists wouldeffectively compete for ligands, presumably naturally occurringhemopoietins including and not limited to IL-3, GM-CSF and IL-5, whichmight trigger or augment the growth of cancer cells by virtue of theirability to bind to the IL-3 receptor complex while intrinsic activationproperties of the ligand are diminished. IL-3, GM-CSF and/or IL-5 alsoplay a role in certain asthmatic responses. An antagonist of the IL-3receptor may have the utility in this disease by blockingreceptor-mediated activation and recruitment of inflammatory cells.

In addition to the use of the IL-3 variants of the present inventionwith other colony stimulating factors in vivo, it is envisioned that invitro uses would include the ability to stimulate bone marrow and bloodcell activation and growth before infusion into patients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the human IL-3 gene for E.coli expression (pMON5873), encodingthe polypeptide sequence of natural (wild type) human IL-3 [SEQ IDNO:128], plus an initiator methionine, as expressed in E. coli, with theamino acids numbered from the N-terminus of the natural hIL-3.

FIG. 2 shows the synergistic effects, in the methylcellulose assay, ofthe IL-3 variant, pMON13288, with G-CSF compared to the synergy ofnative IL-3 with G-CSF . Also shown are the effects of native IL-3 andthe IL-3 variant, pMON13288, alone. The concentration of IL-3 is plottedversus the colony counts per 100,000 starting CD34+ cells.

FIG. 3 shows the synergistic effects, in the methylcellulose assay, ofthe IL-3 variant, pMON13288, with GM-CSF compared to the synergy ofnative IL-3 with GM-CSF . Also shown are the effects of native IL-3 andthe IL-3 variant, pMON13288, alone. The concentration of IL-3 is plottedversus the colony counts per 100,000 starting CD34+ cells.

FIG. 4 shows the synergistic effects, in the cord blood assay, of theIL-3 variant, pMON13288, with stem cell factor (SCF) compared to thesynergy of native IL-3 (pMON5873) with stem cell factor (SCF). Alsoshown are the effects of native IL-3 (pMON5873) and the IL-3 variant,pMON13288, alone. The concentration of IL-3 is plotted versus the colonycounts (CFU) per 10,000 starting CD34+ cells.

FIG. 5 shows the synergistic effects, in the cord blood assay, of theIL-3 variant, pMON13288, with stem cell factor (SCF) compared to thesynergy of native IL-3 (PMON5873) with stem cell factor (SCF). Alsoshown are the effects of native IL-3 (PMON5873) and the IL-3 variant,pMON13288, alone. The concentration of IL-3 is plotted versus the colonycounts (CFU) per 10,000 starting CD34+ cells.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses the coadministration or sequentialtreatment with recombinant human interleukin-3 (hIL-3) variant or mutantproteins (muteins) with other colony stimulating factors (CSFs),cytokines, lymphokines, interleukins, hematopoietic growth factors andvariants thereof (herein after collectively referred to as "colonystimulating factors"). This invention encompasses the coadministrationor sequential treatment using IL-3 variants and other colony stimulatingfactors colony stimulating factors, each of which may act through adifferent and specific cell receptor to initiate complementarybiological activities. Hematopoiesis requires a complex series ofcellular events in which stem cells generate continuously into largepopulations of maturing cells in all major lineages. There are currentlyat least 20 known regulators with hematopoietic proliferative activity.Most of these proliferative regulators can stimulate one or another typeof colony formation in vitro, the precise pattern of colony formationstimulated by each regulator is quite distinctive. No two regulatorsstimulate exactly the same pattern of colony formation, as evaluated bycolony numbers or, more importantly, by the lineage and maturationpattern of the cells making up the developing colonies. Proliferativeresponses can most readily be analyzed in simplified in vitro culturesystems. Three quite different parameters can be distinguished:alteration in colony size, alteration in colony numbers and celllineage. Two or more factors may act on the progenitor cell, inducingthe formation of larger number of progeny thereby increasing the colonysize. Two or more factors may allow increased number of progenitor cellsto proliferate either because distinct subsets of progenitors cellsexist that respond exclusively to one factor or because some progenitorsrequire stimulation by two or more factors before being able to respond.Activation of additional receptors on a cell by the use of two or morefactors is likely to enhance the mitotic signal because of coalescenceof initially differing signal pathways into a common final pathwayreaching the nucleus (Metcalf, 1989). Other mechanism could explainsynergy. For example, if one signaling pathway is limited by anintermediate activation of an additional signaling pathway by a secondfactor may result in a superadditive response. In some cases, activationof one receptor type can induce an enhanced expression of otherreceptors (Metcalf, 1993). Two or more factors may result in a differentpattern of cell lineages then from a single factor. The use of the IL-3variants of the present invention with other colony stimulating factorsmay have the potential clinical advantage resulting from a proliferativeresponse that is not possible by any single factor.

Hematopoietic and other growth factors can be grouped in to two distinctfamilies of related receptors: (1) tyrosine kinase receptors, includingthose for epidermal growth factor, M-CSF (Sherr, 1990) and SCF (Yardenet al., 1987): and (2) hematopoietic receptors, not containing atyrosine kinase domain, but exhibiting obvious homology in theirextracellular domain (Bazan, 1990). Included in the later group areerythropoietin (D'Andrea et al., 1989), GM-CSF (Gearing et al., 1989),IL-3 (Kitamura et al., 1991), G-CSF (Fukunaga et al., 1990), IL-4(Harada et al., 1990), IL-5 (Takaki et al., 1990), IL-6 (Yamasaki etal., 1988), IL-7 (Goodwin et al., 1990), LIF (Gearing et al., 1991) andIL-2 (Cosman et al., 1987). Most of the later group of receptors existsin high-affinity form as a heterodimers. After ligand binding, thespecific α-chains become associated with at least one other receptorchain (β-chain, γ-chain). Many of these factors share a common receptorsubunit. The α-chains for GM-CSF, IL-3 and IL-5 share the same β-chain(Kitamura et al., 1991) and receptor complexes for IL-6, LIF and IL-11share a common β-chain (gp130) (Taga et al., 1989; Gearing et al.,1992). The receptor complexes of IL-2, IL-4 and IL-7 share a commonγ-chain (Kondo et al., 1993; Russell et al., 1993; Noguchi et al.,1993).

GM-CSF accelerates recovery of neutrophils and maintains functionalcapacity, yet has little demonstrable effect on platelet recovery. Incontrast IL-3 promotes a slower increase recovery in neutrophils andmonocytes while accelerating the recovery of platelets.

Recent studies in normal primates indicate that when IL-3 wasadministered before GM-CSF that the combination of IL-3 and GM-CSFpromoted a synergistic rise in peripheral white blood cells andplatelets (Donahue R. E. et al., 1988; Krumwieh D. et al., 1988; andStahl C. P. et al., 1992). The synergistic effect observed in thesequential combination of IL-3 before GM-CSF may result from theexpansion of GM-CSF sensitive cells by IL-3 resulting in a moreefficient production of neutrophils. The coadministration of GM-CSF andIL-3 resulted in diminished neutrophils production relative to GM-CSFalone (Farese et al., 1993). The coadministration of IL-3 and GM-CSF,may result in down regulation of GM-CSF receptors by IL-3 therebydampening the GM-CSF induced increase in neutrophils. However thecoadministration of IL-3 and GM-CSF in a marrow-ablated rhesus monkeyspromoted accelerated platelets and neutrophil recovery relative tosequential cytokine treatment or with either IL-3 or GM-CSF alone(Farese et al., 1993).

The in vitro activity of both IL-3 and GM-CSF has been shown to beadditive with respect to stimulating larger colonies than eithercytokine alone (Robinson et al., 1987; Bruno et al., 1989; Metcalf etal., 1992; Bruno et al., 1991; Bridell et al., 1990). Recently IL-12 hasbeen shown to synergize with IL-3 and c-kit (stem cell factor) toenhance the recovery of hemopoietic stem cells in liquid culture(Ploemacher et al., 1993).

Recent in vitro (Emerson et al., 1988: Sonodo et al., 1988) and in vivo(Ganser et al., 1992; Donahue R. E. et al., 1988; Krumwieh D. et al.,1988; and Stahl C. P. et al., 1992) results of combined IL-3 and GM-CSFtreatment suggests an increased clinical efficacy in cytokinecombination treatment.

As mentioned earlier some of the factors that are involved inhematopoiesis are limited to a specific cell lineage and others havemuch broader effects and may result in the proliferation and support ofmulti-lineages and there may be considerable overlap between thesefactors but that the proliferative profiles are distinct. This suggeststhat the coadministration or sequential treatment with multiple factorsmay have a clinical advantage. IL-3 variants of the present inventionthat have an increased therapeutic index, compared to native IL-3, mayhave a distinct clinical advantage when coadministered or usedsequentially in treatment.

The use of multiple factors may also have potential advantage bylowering the demands placed on factor-producing cells and theirinduction systems. If there are limitations in the ability of a cell toproduce a factor then by lowering the required concentrations of each ofthe factors by using them in combination may usefully reduce demands onthe factor-producing cells. The use of multiple factors may lower theamount of the factors that would be needed, probably reducing thelikelihood of adverse responses.

A non-exclusive list of growth factors, colony stimulating factors(CSFs) including; cytokines, lymphokines, interleukins, hematopoieticgrowth factors, which can be used in coadministration or sequentialtreatment with the hIL-3 variant of the present invention includeGM-CSF, CSF-1, G-CSF, Meg-CSF (more recently referred to as c-mplligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3/flk2, humangrowth hormone, B-cell growth factor, B-cell differentiation factor,eosinophil differentiation factor and stem cell factor (SCF) also knownas steel factor or c-kit ligand and variants thereof.

The present invention relates to novel variants of human interleukin-3(hIL-3) in which amino acid substitutions have been made at four or morepositions in amino acid sequence of the polypeptide used in sequentialtreatment or coadministration with other colony stimulating factors.Preferred IL-3 variants of the present invention which have deletions ofamino acids 1 to 14 at the N-terminus and 126 to 133 at the C-terminusand which also have four or more amino acid substitutions in thepolypeptide used in coadministered or sequential treatment with othercolony stimulating factors or IL-3 variants. Among the preferred IL-3variants are those having twenty-six amino acid substitutions. Thepresent invention includes mutant polypeptides comprising minimallyamino acids 15 to 118 of hIL-3 with or without additional amino acidextensions to the N-terminus and/or C-terminus which further containfour or more amino acid substitutions in the amino acid sequence of thepolypeptide.

As used herein human interleukin-3 corresponds to the amino acidsequence (1-133) as depicted in FIG. 1 and (15-125) hIL-3 corresponds tothe 15 to 125 amino acid sequence of the hIL-3 polypeptide. Naturallyoccurring variants of hIL-3 polypeptide amino acids are also included inthe present invention (for example, the allele in which proline ratherthan serine is at position 8 in the hIL-3 polypeptide sequence) as arevariant hIL-3 molecules which are modified post-translationally (e.g.glycosylation).

"Mutant amino acid sequence," "mutant protein" or "mutant polypeptide"refers to a polypeptide having an amino acid sequence which varies froma native sequence or is encoded by a nucleotide sequence intentionallymade variant from a native sequence. "Mutant protein," "variant protein"or "mutein" means a protein comprising a mutant amino acid sequence andincludes polypeptides which differ from the amino acid sequence ofnative hIL-3 due to amino acid deletions, substitutions, or both."Native sequence" refers to an amino acid or nucleic acid sequence whichis identical to a wild-type or native form of a gene or protein.

Human IL-3 can be characterized by its ability to stimulate colonyformation by human hematopoietic progenitor cells. The colonies formedinclude erythroid, granulocyte, megakaryocyte, granulocytic macrophagesand mixtures thereof. Human IL-3 has demonstrated an ability to restorebone marrow function and peripheral blood cell populations totherapeutically beneficial levels in studies performed initially inprimates and subsequently in humans (Gillio, A. P., et al. (1990);Ganser, A, et al. (1990); Falk, S., et al. (1991). Additional activitiesof hIL-3 include the ability to stimulate leukocyte migration andchemotaxis; the ability to prime human leukocytes to produce high levelsof inflammatory mediators like leukotrienes and histamine; the abilityto induce cell surface expression of molecules needed for leukocyteadhesion; and the ability to trigger dermal inflammatory responses andfever. Many or all of these biological activities of hIL-3 involvesignal transduction and high affinity receptor binding. Coadministrationor sequential treatment using the IL-3 variants of the present inventionwith other colony stimulating factors may exhibit useful properties suchas having similar or greater biological activity when compared to nativehIL-3 or by having improved half-life or decreased adverse side effects,or a combination of these properties. The IL-3 variants of the presentinvention may also be useful as antagonists. IL-3 variants which havelittle or no activity when compared to native hIL-3 may still be usefulas antagonists, as antigens for the production of antibodies for use inimmunology or immunotherapy, as genetic probes or as intermediates usedto construct other useful hIL-3 muteins.

The use of IL-3 variants of the present invention when coadministered oras part of sequential treatment will preferably have at least onebiological property of human IL-3. Coadministration or sequentialtreatment may also have more than one IL-3-like biological property, oran improved property, or a reduction in an undesirable biologicalproperty of human IL-3. Some mutant polypeptides of the presentinvention may also exhibit an improved side effect profile. For example,they may exhibit a decrease in leukotriene release or histamine releasewhen compared to native hIL-3 or (15-125) hIL-3. Such hIL-3 orhIL-3-like biological properties may include one or more of thefollowing biological characteristics and in vivo and in vitroactivities.

One such property is the support of the growth and differentiation ofprogenitor cells committed to erythroid, lymphoid, and myeloid lineages.For example, in a standard human bone marrow assay, an IL-3-likebiological property is the stimulation of granulocytic type colonies,megakaryocytic type colonies, monocyte/macrophage type colonies, anderythroid bursts. Other IL-3-like properties are the interaction withearly multipotential stem cells, the sustaining of the growth ofpluripotent precursor cells, the ability to stimulate chronicmyelogenous leukemia (CML) cell proliferation, the stimulation ofproliferation of mast cells, the ability to support the growth ofvarious factor-dependent cell lines, and the ability to trigger immaturebone marrow cell progenitors. Other biological properties of IL-3 havebeen disclosed in the art. Human IL-3 also has some biologicalactivities which may in some cases be undesirable, for example theability to stimulate leukotriene release and the ability to stimulateincreased histamine synthesis in spleen and bone marrow cultures and invivo.

Biological activity of hIL-3 and hIL-3 variant proteins of the presentinvention is determined by DNA synthesis by human acute myelogenousleukemia cells (AML). The factor-dependent cell line AML 193 was adaptedfor use in testing biological activity. The biological activity of hIL-3and hIL-3 variant proteins of the present invention is also determinedby counting the colony forming units in a bone marrow assay.

Other in vitro cell based assays may also be useful to determine thesynergistic effect of multiple colony stimulating factors that comprisethe mixture. The following are examples of other useful assays.

TF-1 proliferation assay: The TF-1 cell line was derived from bonemarrow of a patient with erythroleukemia (Kitamura et al., 1989). TF-1cells respond to IL-3, GM-CSF, EPO and IL-5. 32D proliferation assay:32D is a murine IL-3 dependent cell line which does not respond to humanIL-3 but does respond to human G-CSF which is not species restricted.

T1165 proliferation assay: T1165 cells are a IL-6 dependent murine cellline (Nordan et al., 1986) which respond to IL-6 and IL-11.

Human Plasma Clot meg-CSF Assay: Used to assay megakaryocyte colonyformation activity (Mazur et al., 1981).

One object of the present invention is to provide hIL-3 variant withfour or more amino acid substitutions in the polypeptide sequence usedin coadministration or sequential treatment with other colonystimulating factors or IL-3 variants, which have similar or improvedbiological activity in relation to native hIL-3 or the other colonystimulating factors or IL-3 variant.

The hIL-3 variants of the present invention may have hIL-3 or hIL-3-likeactivity. For example, they may possess one or more of the biologicalactivities of native hIL-3 and may be useful in stimulating theproduction of hematopoietic cells by human or primate progenitor cells.The IL-3 variants of the present invention and pharmaceuticalcompositions containing them may be useful in the treatment ofconditions in which hematopoietic cell populations have been reduced ordestroyed due to disease or to treatments such as radiation orchemotherapy. Pharmaceutical compositions containing IL-3 variants ofthe present invention can be administered parenterally, intravenously,or subcutaneously.

Native hIL-3 possesses considerable inflammatory activity and has beenshown to stimulate synthesis of the arachidonic acid metabolites LTC4,LTD4, and LTE4; histamine synthesis and histamine release. Humanclinical trials with native hIL-3 have documented inflammatory responses(Biesma, et al., BLOOD, 80:1141-1148 (1992) and Postmus, et al., J.CLIN. ONCOL., 10:1131-1140 (1992)). A recent study indicates thatleukotrienes were involved in IL-3 actions in vivo and ay contributesignificantly to the biological effects of IL-3 treatment (Denzlinger,C., et al., BLOOD, 81:2466-2470 (1993))

Some IL-3 variants of the present invention, when co-administered withother CSFs, cytokines, lymphokines, interleukins, hematopoietic growthfactors or IL-3 variants, may have an improved therapeutic profile ascompared to native hIL-3 or (15-125)hIL-3. For example, some IL-3variants of the present invention may have a similar or more potentgrowth factor activity relative to native hIL-3 or (15-125)hIL-3 withouthaving a similar or corresponding increase in the stimulation ofleukotriene or histamine. These IL-3 variants would be expected to havea more favorable therapeutic profile since the amount of polypeptidewhich needs to be given to achieve the desired growth factor activity(e.g. cell proliferation) would have a diminished leukotriene orhistamine stimulating effect. In studies with native hIL-3, thestimulation of inflammatory factors has been an undesirable side effectof the treatment. Reduction or elimination of the stimulation ofmediators of inflammation would provide an advantage over the use ofnative hIL-3.

Novel IL-3 variants of the present invention may also be useful asantagonists which block the hIL-3 receptor by binding specifically to itand preventing binding of the agonist.

One potential advantage of the novel IL-3 variants of the presentinvention, particularly those which retain activity similar to or betterthan that of native hIL-3, is that it may be possible to use a smalleramount of the biologically active mutein to produce the desiredtherapeutic effect. This may make it possible to reduce the number oftreatments necessary to produce the desired therapeutic effect. The useof smaller amounts may also reduce the possibility of any potentialantigenic effects or other possible undesirable side effects. Forexample, if a desired therapeutic effect can be achieved with a smalleramount of polypeptide it may be possible to reduce or eliminate sideeffects associated with the administration of native IL-3 such as thestimulation of leukotriene and/or histamine release. The novel IL-3variants of the present invention may also be useful in the activationof stem cells or progenitors which have low receptor numbers.

Compounds of this invention are preferably made by genetic engineeringtechniques now standard in the art U.S. Pat. No. 4,935,233 and Sambrooket al., "Molecular Cloning. A Laboratory Manual", Cold Spring HarborLaboratory (1989)]. One method of creating the preferred hIL-3 (15-125)mutant genes is cassette mutagenesis [Wells, et al. (1985)] in which aportion of the coding sequence of hIL-3 in a plasmid is replaced withsynthetic oligonucleotides that encode the desired amino acidsubstitutions in a portion of the gene between two restriction sites. Ina similar manner amino acid substitutions could be made in thefull-length hIL-3 gene, or genes encoding variants of hIL-3 in whichfrom 1 to 14 amino acids have been deleted from the N-terminus and/orfrom 1 to 15 amino acids have been deleted from the C-terminus. Whenproperly assembled these oligonucleotides would encode hIL-3 variantswith the desired amino acid substitutions and/or deletions from theN-terminus and/or C-terminus. These and other mutations could be createdby those skilled in the art by other mutagenesis methods including;oligonucleotide-directed mutagenesis [Zoller and Smith (1982, 1983,1984), Smith (1985), Kunkel (1985), Taylor, et al. (1985), Deng andNickoloff (1992)] or polymerase chain reaction (PCR) techniques [Saiki,(1985)].

Plasmid DNA can be treated with the chosen restriction endonucleasesthen ligated to the annealed oligonucleotides. The ligated mixtures canbe used to transform competent JMlOl cells to resistance to anappropriate antibiotic. Single colonies can be picked and the plasmidDNA examined by restriction analysis and/or DNA sequencing to identifyplasmids with mutant hIL-3 genes.

Suitable cells or cell lines for the production of the proteins claimedin the present invention may be bacterial cells. For example, thevarious strains of E. coli are well-known as host cells in the field ofbiotechnology. Examples of such strains include E. coli strains JM101[Yanish-Perron, et al. (1985)] and MON105 [Obukowicz, et al. (1992)].Also included in the present invention is the expression of the IL-3variant protein utilizing a chromosomal expression vector for E. colibased on the bacteriophage Mu (Weinberg et al., 1993). Various strainsof B. subtilis may also be employed as host cells for expression of thepolypeptides of the present invention. Many strains of yeast cells knownto those skilled in the art are also available as host cells forexpression of the polypeptides of the present invention. When expressedin the E. coli cytoplasm, the above-mentioned mutant hIL-3 variants ofthe present invention may also be constructed with Met-Ala- at theN-terminus so that upon expression the Met is cleaved off leaving Ala atthe N-terminus. The IL-3 variant proteins of the present invention mayinclude polypeptides having Met-, Ala- or Met-Ala- attached to theN-terminus. When the IL-3 variant polypeptides are expressed in thecytoplasm of E. coli, polypeptides with and without Met attached to theN-terminus are obtained. The N-termini of proteins made in the cytoplasmof E. coli are affected by posttranslational processing by methionineaminopeptidase (Ben-Bassat et al., 1987) and possibly by otherpeptidases. These IL-3 variant proteins may also be expressed in E. coliby fusing a signal peptide to the N-terminus. This signal peptide iscleaved from the polypeptide as part of the secretion process. Secretionin E. coli can be used to obtain the correct amino acid at theN-terminus (e.g., Asn¹⁵ in the (15-125) hIL-3 polypeptide) due to theprecise nature of the signal peptidase. This is in contrast to theheterogeneity which may be observed at the N-terminus of proteinsexpressed in the cytoplasm in E. coli.

Also suitable for use in the present invention are mammalian cells, suchas Chinese hamster ovary cells (CHO). General methods for expression offoreign genes in mammalian cells are reviewed in: Kaufman, R. J. (1987)High level production of proteins in mammalian cells, in GeneticEngineering, Principles and Methods, Vol. 9, J. K. Setlow, editor,Plenum Press, New York. An expression vector is constructed in which astrong promoter capable of functioning in mammalian cells drivestranscription of a eukaryotic secretion signal peptide coding region,which is translationally fused to the coding region for the IL-3variant. For example, plasmids such as pcDNA I/Neo, pRc/RSV, and pRc/CMV(obtained from Invitrogen Corp., San Diego, Calif.) can be used. Theeukaryotic secretion signal peptide coding region can be from the hIL-3gene itself or it can be from another secreted mammalian protein (Bayne,M. L. et al. (1987) Proc. Natl. Acad. Sci. USA 84, 2638-2642). Afterconstruction of the vector containing the hIL-3 variant gene, the vectorDNA is transfected into mammalian cells. Such cells can be, for example,the COS7, HeLa, BHK, CHO, or mouse L lines. The cells can be cultured,for example, in DMEM media (JRH Scientific). The hIL-3 variant secretedinto the media can be recovered by standard biochemical approachesfollowing transient expression 24-72 hours after transfection of thecells or after establishment of stable cell lines following selectionfor neomycin resistance. The selection of suitable mammalian host cellsand methods for transformation, culture, amplification, screening andproduct production and purification are known in the art. See, e.g.,Gething and Sambrook, Nature, 293:620-625 (1981), or alternatively,Kaufman et al, Mol. Cell. Biol., 5(7):1750-1759 (1985) or Howley et al.,U.S. Pat. No. 4,419,446. Another suitable mammalian cell line is themonkey COS-1 cell line. A similarly useful mammalian cell line is theCV-1 cell line.

Where desired, insect cells may be utilized as host cells in the methodof the present invention. See, e.g. Miller et al, Genetic Engineering,8:277-298 (Plenum Press 1986) and references cited therein. In addition,general methods for expression of foreign genes in insect cells usingBaculovirus vectors are described in: Summers, M. D. and Smith, G. E.(1987)--A manual of methods for Baculovirus vectors and insect cellculture procedures, Texas Agricultural Experiment Station Bulletin No.1555. An expression vector is constructed comprising a Baculovirustransfer vector, in which a strong Baculovirus promoter (such as thepolyhedron promoter) drives transcription of a eukaryotic secretionsignal peptide coding region, which is translationally fused to thecoding region for the IL-3 variant polypeptide. For example, the plasmidpVL1392 (obtained from Invitrogen Corp., San Diego, California) can beused. After construction of the vector carrying the gene encoding theIL-3 variant polypeptide, two micrograms of this DNA is cotransfectedwith one microgram of Baculovirus DNA (see Summers & Smith, 1987) intoinsect cells, strain SF9. Pure recombinant Baculovirus carrying the IL-3variant gene is used to infect cells cultured, for example, in Excell401 serum-free medium (JRH Biosciences, Lenexa, Kansas). The IL-3variant protein secreted into the medium can be recovered by standardbiochemical approaches. Supernatants from mammalian or insect cellsexpressing the IL-3 variant protein can be first concentrated using anyof an number of commercial concentration units.

Coadministration or sequential treatment using IL-3 variants of thepresent invention with other colony stimulating factors may be useful inthe treatment of diseases characterized by a decreased levels of eithermyeloid, erythroid, lymphoid, or megakaryocyte cells of thehematopoietic system or combinations thereof. In addition, they may beused to activate mature myeloid and/or lymphoid cells. Among conditionssusceptible to treatment with the polypeptides of the present inventionis leukopenia, a reduction in the number of circulating leukocytes(white cells) in the peripheral blood. Leukopenia may be induced byexposure to certain viruses or to radiation. It is often a side effectof various forms of cancer therapy, e.g., exposure to chemotherapeuticdrugs, radiation and of infection or hemorrhage. Therapeutic treatmentof leukopenia with these IL-3 variants of the present invention withother colony stimulating factors may avoid undesirable side effectscaused by treatment with presently available drugs.

Coadministration or sequential treatment using IL-3 variants of thepresent invention with other colony stimulating factors may be useful inthe treatment of neutropenia and, for example, in the treatment of suchconditions as aplastic anemia, cyclic neutropenia, idiopathicneutropenia, Chediak-Higashi syndrome, systemic lupus erythematosus(SLE), leukemia, myelodysplastic syndrome and myelofibrosis.

The IL-3 variants of the present invention, when coadministered or usedin sequential treatment with other colony stimulating factors, may beuseful in the treatment or prevention of thrombocytopenia. Currently theonly therapy for thrombocytopenia is platelet transfusions which arecostly and carry the significant risks of infection (HIV, HBV) andalloimunization. The IL-3 variants, when coadministered or used insequential treatment with other colony stimulating factors, mayalleviate or diminish the need for platelet transfusions. Severethrombocytopenia may result from genetic defects such as Fanconi'sAnemia, Wiscott-Aldrich, or May-Hegglin syndromes. Acquiredthrombocytopenia may result from auto- or allo-antibodies as in ImmuneThrombocytopenia Purpura, Systemic Lupus Erythromatosis, hemolyticanemia, or fetal maternal incompatibility. In addition, splenomegaly,disseminated intravascular coagulation, thrombotic thrombocytopenicpurpura, infection or prosthetic heart valves may result inthrombocytopenia. Severe thrombocytopenia may also result fromchemotherapy and/or radiation therapy or cancer. Thrombocytopenia mayalso result from marrow invasion by carcinoma, lymphoma, leukemia orfibrosis.

The IL-3 variants of the present invention, when coadministered or usedin sequential treatment with other colony stimulating factors, may beuseful in the mobilization of hematopoietic progenitors and stem cellsinto peripheral blood. Peripheral blood derived progenitors have beenshown to be effective in reconstituting patients in the setting ofautologous marrow transplantation. Hematopoietic growth factorsincluding G-CSF and GM-CSF have been shown to enhance the number ofcirculating progenitors and stem cells in the peripheral blood. This hassimplified the procedure for peripheral stem cell collection anddramatically decreased the cost of the procedure by decreasing thenumber of pheresis required. The IL-3 variants, when coadministered orused in sequential treatment with other colony stimulating factors, maybe useful in mobilization of stem cells and further enhance the efficacyof peripheral stem cell transplantation.

Another projected clinical use of growth factors has been in the invitro activation of hematopoietic progenitors and stem cells for genetherapy. In order to have the gene of interest incorporated into thegenome of the hematopoietic progenitor or stem cell one needs tostimulate cell division and DNA replication. Hematopoietic stem cellscycle at a very low frequency which means that growth factors may beuseful to promote gene transduction and thereby enhance the clinicalprospects for gene therapy.

Many drugs may cause bone marrow suppression or hematopoieticdeficiencies. Examples of such drugs are AZT, DDI, alkylating agents andanti-metabolites used in chemotherapy, antibiotics such aschloramphenicol, penicillin, gancyclovir, daunomycin and sulfa drugs,phenothiazones, tranquilizers such as meprobamate, analgesics such asaminopyrine and dipyrone, anticonvulsants such as phenytoin orcarbamazepine antithyroids such as propylthiouracil and methimazole anddiuretics. Coadministration or sequential treatment using IL-3 variantsof the present invention with other colony stimulating factors may beuseful in preventing or treating the bone marrow suppression orhematopoietic deficiencies which often occur in patients treated withthese drugs.

Hematopoietic deficiencies may also occur as a result of viral,microbial or parasitic infections and as a result of treatment for renaldisease or renal failure, e.g., dialysis. Coadministration or sequentialtreatment using IL-3 variants of the present invention with other colonystimulating factors may be useful in treating such hematopoieticdeficiency.

The treatment of hematopoietic deficiency may include administration ofa pharmaceutical composition containing the IL-3 variants with othercolony stimulating factors to a patient. Coadministration or sequentialtreatment using IL-3 variants of the present invention with other colonystimulating factors may also be useful for the activation andamplification of hematopoietic precursor cells by treating these cellsin vitro with the coadministration or sequential treatment using IL-3variants of the present invention with other colony stimulating factorsprior to injecting the cells into a patient.

Various immunodeficiencies e.g., in T and/or B lymphocytes, or immunedisorders, e.g., rheumatoid arthritis, may also be beneficially affectedby treatment with the coadministration or sequential treatment usingIL-3 variants of the present invention with other colony stimulatingfactors molecules of the present invention. Immunodeficiencies may bethe result of viral infections e.g. HTLVI, HTLVII, HTLVIII, severeexposure to radiation, cancer therapy or the result of other medicaltreatment. IL-3 variants of the present invention may also be employed,alone or in combination with other hematopoietins, in the treatment ofother blood cell deficiencies, including thrombocytopenia (plateletdeficiency), or anemia. Other uses for these novel polypeptides are inthe treatment of patients recovering from bone marrow transplants invivo and ex vivo, and in the development of monoclonal and polyclonalantibodies generated by standard methods for diagnostic or therapeuticuse.

Other aspects of the present invention are methods and therapeuticcompositions for treating the conditions referred to above. Suchcompositions comprise a therapeutically effective amount of one or moreof the IL-3 variants of the present invention with other colonystimulating factors in a mixture with a pharmaceutically acceptablecarrier. This composition can be administered either parenterally,intravenously or subcutaneously. When administered, the therapeuticcomposition for use in this invention is preferably in the form of apyrogen-free, parenterally acceptable aqueous solution. The preparationof such a parenterally acceptable protein solution, having due regard topH, isotonicity, stability and the like, is within the skill of the art.

The dosage regimen involved in a method for treating the above-describedconditions will be determined by the attending physician consideringvarious factors which modify the action of drugs, e.g. the condition,body weight, sex and diet of the patient, the severity of any infection,time of administration and other clinical factors. Generally, a dailyregimen may be in the range of 0.2-150 μg/kg of IL-3 variant protein perkilogram of body weight. This dosage regimen is referenced to a standardlevel of biological activity which recognizes that native IL-3 generallypossesses an EC₅₀ at or about 10 picoMolar to 100 picoMolar in the AMLproliferation assay described herein. Therefore, dosages would beadjusted relative to the activity of a given IL-3 variant protein vs.the activity of native (reference) IL-3 and it would not be unreasonableto note that dosage regimens may include doses as low as 0.1 microgramand as high as 1 milligram per kilogram of body weight per day. Inaddition, there may exist specific circumstances where dosages of IL-3variant protein would be adjusted higher or lower than the range of10-200 micrograms per kilogram of body weight. These includeco-administration with other CSF, cytokine, lymphokine, interleukin,hematopoietic growth factor or IL-3 variant or growth factors;co-administration with chemotherapeutic drugs and/or radiation; the useof glycosylated IL-3 proteins; and various patient-related issuesmentioned earlier in this section. As indicated above, the therapeuticmethod and compositions may also include co-administration with otherhuman factors. A non-exclusive list of other appropriate hematopoietins,CSFs, cytokines, lymphokines, hematopoietic growth factors andinterleukins for simultaneous or serial co-administration with thepolypeptides of the present invention includes GM-CSF, CSF-1, G-CSF,Meg-CSF (more recently referred to as c-mpl ligand), M-CSF,erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, IL-13, LIF, flt3/flk2, human growth hormone, B-cellgrowth factor, B-cell differentiation factor and eosinophildifferentiation factor, stem cell factor (SCF) also known as steelfactor or c-kit ligand, or combinations thereof. The dosage recitedabove would be adjusted to compensate for such additional components inthe therapeutic composition. Progress of the treated patient can bemonitored by periodic assessment of the hematological profile, e.g.,differential cell count and the like.

The present invention includes the following compositions:

1. A composition comprising:

A human interleukin-3 mutant polypeptide of the Formula:

    Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn                                                       [SEQ ID NO:1]                              1               5                   10                  15                   Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    20                  25                  30                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa                                    35                  40                  45                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    50                  55                  60                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    65                  70                  75                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    80                  85                  90                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    95                 100                 105                   Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                   110                 115                 120                   Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe                                           125                 130                                   

wherein

Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;

Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;

Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;

Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;

Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr,Ser or Val;

Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln, Leu,Val or Gly;

Xaa at position 23 is Ile, Val, Ala, Leu, Gly, Trp, Lys, Phe, Leu, Ser,or Arg;

Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;

Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;

Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;

Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;

Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;

Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;

Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;

Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;

Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;

Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;

Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr, Arg, Ala,Phe, Ile or Met;

Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;

Xaa at position 36 is Asp, Leu, or Val;

Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;

Xaa at position 38 is Asn, or Ala;

Xaa at position 40 is Leu, Trp, or Arg;

Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;

Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu,Phe, Tyr, Ile, Met or Ala;

Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg,Thr, Gly or Ser;

Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn,Gln, Ala or Pro;

Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp,Asn, Arg, Ser, Ala, Ile, Glu or His;

Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly;

Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;

Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr,Ala, Met, Val or Asn;

Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;

Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile,Val, His, Phe, Met or Gln;

Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;

Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;

Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;

Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His,Ala or Leu;

Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;

Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His, Thr, Ala,Tyr, Phe, Leu, Val or Lys;

Xaa at position 57 is Asn or Gly;

Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;

Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;

Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;

Xaa at position 62 is Asn His, Val, Arg, Pro, Thr, Asp, or Ile;

Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;

Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;

Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;

Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;

Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;

Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;

Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;

Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;

Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, orAsn;

Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;

Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;

Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;

Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gln, orLeu;

Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;

Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;

Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;

Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;

Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;

Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr,Ser, Ala, Tyr, Phe, Ile, Met or Val;

Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;

Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;

Xaa at position 85 is Leu, Asn, Val, or Gln;

Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;

Xaa at position 87 is Leu, Ser, Trp, or Gly;

Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;

Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;

Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;

Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;

Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile orLeu;

Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;

Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His, Ala,or Pro;

Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys,Ser, Ala, Trp, Phe, Ile, or Tyr;

Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;

Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;

Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser,Phe, Met, Val, Lys, Arg, Tyr or Pro;

Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln, Gly, Ser, Phe,or His;

Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;

Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn,Ser, Ala, Gly, Ile, Leu, or Gln;

Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;

Xaa at position 103 is Asp, or Ser;

Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly;

Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys,Ile, Asp, or His;

Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;

Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser, Alaor Pro;

Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;

Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser,Ala, or Trp;

Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;

Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;

Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu,Ile, Val or Asn;

Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;

Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, orMet;

Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp,Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;

Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;

Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;

Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;

Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;

Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;

Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,or Cys;

Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;

and which can additionally have Met- preceding the amino acid inposition 1; and wherein from 1 to 14 amino acids can be deleted from theN-terminus and/or from 1 to 15 amino acids can be deleted from theC-terminus; and wherein from 4 to 44 of the amino acids designated byXaa are different from the corresponding amino acids of native (1-133)human interleukin-3;

A colony stimulating factor selected from the group consisting ofGM-CSF, CSF-1, G-CSF, Meg-CSF (more recently referred to as c-mplligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3/flk2, humangrowth hormone, B-cell growth factor, B-cell differentiation factor,eosinophil differentiation factor and stem cell factor (SCF); and

At least one non-toxic pharmaceutically acceptable carrier.

2 A composition, comprising: A human interleukin-3 mutant polypeptide ofthe Formula:

    Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn                                                       [SEQ ID NO:2]                              1               5                   10                  15                   Cys Xaa Xaa Xaa Ile Xaa Glu Xaa Xaa Xaa Xaa Leu Lys Xaa Xaa                                    20                  25                  30                   Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Asn Leu Asn Xaa Glu Xaa Xaa                                    35                  40                  45                   Xaa Ile Leu Met Xaa Xaa Asn Leu Xaa Xaa Xaa Asn Leu Glu Xaa                                    50                  55                  60                   Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Ile Glu                                    65                  70                  75                   Xaa Xaa Leu Xaa Xaa Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Thr Ala                                    80                  85                  90                   Xaa Pro Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa Xaa                                    95                 100                 105                   Xaa Phe Xaa Xaa Lys Leu Xaa Phe Xaa Xaa Xaa Xaa Leu Glu Xaa                                   110                 115                 120                   Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe                                           125                 130                                   

wherein

Xaa at position 17 is Ser, Gly, Asp, Met, or Gln;

Xaa at position 18 is Asn, His, or Ile;

Xaa at position 19 is Met or Ile;

Xaa at position 21 is Asp or Glu;

Xaa at position 23 is Ile, Ala, Leu, or Gly;

Xaa at position 24 is Ile, Val, or Leu;

Xaa at position 25 is Thr, His, Gln, or Ala;

Xaa at position 26 is His or Ala;

Xaa at position 29 is Gln, Asn, or Val;

Xaa at position 30 is Pro, Gly, or Gln;

Xaa at position 31 is Pro, Asp, Gly, or Gln;

Xaa at position 32 is Leu, Arg, Gln, Asn, Gly, Ala, or Glu;

Xaa at position 33 is Pro or Glu;

Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Ala, Arg, Gln, Glu, Ile,Phe, Thr or Met;

Xaa at position 35 is Leu, Ala, Asn, Pro, Gln, or Val;

Xaa at position 37 is Phe, Ser, Pro, or Trp;

Xaa at position 38 is Asn or Ala;

Xaa at position 42 is Gly, Asp, Ser, Cys, Ala, Asn, Ile, Leu, Met, Tyror Arg;

Xaa at position 44 is Asp or Glu;

Xaa at position 45 is Gln, Val, Met, Leu, Thr, Ala, Asn, Glu, Ser orLys;

Xaa at position 46 is Asp, Phe, Ser, Thr, Ala, Asn Gln, Glu, His, Ile,Lys, Tyr, Val or Cys;

Xaa at position 50 is Glu, Ala, Asn, Ser or Asp;

Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;

Xaa at position 54 is Arg or Ala;

Xaa at position 55 is Arg, Thr, Val, Leu, or Gly;

Xaa at position 56 is Pro, Gly, Ser, Gln, Ala, Arg, Asn, Glu, Leu, Thr,Val or Lys;

Xaa at position 60 is Ala or Ser;

Xaa at position 62 is Asn, Pro, Thr, or Ile;

Xaa at position 63 is Arg or Lys;

Xaa at position 64 is Ala or Asn;

Xaa at position 65 is Val or Thr;

Xaa at position 66 is Lys or Arg;

Xaa at position 67 is Ser, Phe, or His;

Xaa at position 68 is Leu, Ile, Phe, or His;

Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, or Gly;

Xaa at position 71 is Ala, Pro, or Arg;

Xaa at position 72 is Ser, Glu, Arg, or Asp;

Xaa at position 73 is Ala or Leu;

Xaa at position 76 is Ser, Val, Ala, Asn, Glu, Pro, or Gly;

Xaa at position 77 is Ile or Leu;

Xaa at position 79 is Lys, Thr, Gly, Asn, Met, Arg, Ile, Gly, or Asp;

Xaa at position 80 is Asn, Gly, Glu, or Arg;

Xaa at position 82 is Leu, Gln, Trp, Arg, Asp, Ala, Asn, Glu, His, Ile,Met, Phe, Ser, Thr, Tyr or Val;

Xaa at position 83 is Pro or Thr;

Xaa at position 85 is Leu or Val;

Xaa at position 87 is Leu or Ser;

Xaa at position 88 is Ala or Trp;

Xaa at position 91 is Ala or Pro;

Xaa at position 93 is Thr, Asp, Ser, Pro, Ala, Leu, or Arg;

Xaa at position 95 is His, Pro, Arg, Val, Leu, Gly, Asn, Phe, Ser orThr;

Xaa at position 96 is Pro or Tyr;

Xaa at position 97 is Ile or Val;

Xaa at position 98 is His, Ile, Asn, Leu, Ala, Thr, Leu, Arg, Gln, Leu,Lys, Met, Ser, Tyr, Val or Pro;

Xaa at position 99 is Ile, Leu, or Val;

Xaa at position 100 is Lys, Arg, Ile, Gln, Pro, or Ser;

Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Pro, Asn, Ile, Leuor Tyr;

Xaa at position 104 is Trp or Leu;

Xaa at position 105 is Asn, Pro, Ala, Ser, Trp, Gln, Tyr, Leu, Lys, Ile,Asp, or His;

Xaa at position 106 is Glu or Gly;

Xaa at position 108 is Arg, Ala, or Ser;

Xaa at position 109 is Arg, Thr, Glu, Leu, or Ser;

Xaa at position 112 is Thr, Val, or Gln;

Xaa at position 114 is Tyr or Trp;

Xaa at position 115 is Leu or Ala;

Xaa at position 116 is Lys, Thr, Val, Trp, Ser, Ala, His, Met, Phe, Tyror Ile;

Xaa at position 117 is Thr or Ser;

Xaa at position 120 is Asn, Pro, Leu, His, Val, or Gln;

Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Asp, or Gly;

Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,or Cys;

Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu.

and which can additionally have Met- preceding the amino acid inposition 1; and wherein from 1 to 14 amino acids can be deleted from theN-terminus and/or from 1 to 15 amino acids can be deleted from theC-terminus; and wherein from 4 to 35 of the amino acids designated byXaa are different from the corresponding amino acids of native(1-133)human interleukin-3;

A colony stimulating factor selected from the group consisting ofGM-CSF, CSF-1, G-CSF, Meg-CSF (more recently referred to as c-mplligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3/flk2, humangrowth hormone, B-cell growth factor, B-cell differentiation factor,eosinophil differentiation factor and stem cell factor (SCF); and

At least one non-toxic pharmaceutically acceptable carrier.

3. A composition of 2, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

    Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn                                                       [SEQ ID NO:3]                              1                5                  10                  15                   Cys Xaa Xaa Met Ile Asp Glu Xaa Ile Xaa Xaa Leu Lys Xaa Xaa                                    20                  25                  30                   Pro Xaa Pro Xaa Xaa Asp Phe Xaa Asn Leu Asn Xaa Glu Asp Xaa                                    35                  40                  45                   Xaa Ile Leu Met Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Glu Ala                                    50                  55                  60                   Phe Xaa Arg Xaa Xaa Lys Xaa Xaa Xaa Asn Ala Ser Ala Ile Glu                                    65                  70                  75                   Xaa Xaa Leu Xaa Xaa Leu Xaa Pro Cys Leu Pro Xaa Xaa Thr Ala                                    80                  85                  90                   Xaa Pro Xaa Arg Xaa Pro Ile Xaa Xaa Xaa Xaa Gly Asp Trp Xaa                                    95                 100                 105                   Glu Phe Xaa Xaa Lys Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu Xaa                                   110                 115                 120                   Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe                                           125                 130                                   

wherein

Xaa at position 17 is Ser, Gly, Asp, or Gln;

Xaa at position 18 is Asn, His, or Ile;

Xaa at position 23 is Ile, Ala, Leu, or Gly;

Xaa at position 25 is Thr, His, or Gln;

Xaa at position 26 is His or Ala;

Xaa at position 29 is Gln or Asn;

Xaa at position 30 is Pro or Gly;

Xaa at position 32 is Leu, Arg, Asn, or Ala;

Xaa at position 34 is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile, Phe, Thr,or Met;

Xaa at position 35 is Leu, Ala, Asn, or Pro;

Xaa at position 38 is Asn or Ala;

Xaa at position 42 is Gly, Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr orArg;

Xaa at position 45 is Gln, Val, Met, Leu, Ala, Asn, Glu, or Lys;

Xaa at position 46 is Asp, Phe, Ser, Gln, Glu, His, Val or Thr;

Xaa at position 50 is Glu Asn, Ser or Asp;

Xaa at position 51 is Asn, Arg, Pro, Thr, or His;

Xaa at position 55 is Arg, Leu, or Gly;

Xaa at position 56 is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln;

Xaa at position 62 is Asn, Pro, or Thr;

Xaa at position 64 is Ala or Asn;

Xaa at position 65 is Val or Thr;

Xaa at position 67 is Ser or Phe;

Xaa at position 68 is Leu or Phe;

Xaa at position 69 is Gln, Ala, Glu, or Arg;

Xaa at position 76 is Ser, Val, Asn, Pro, or Gly;

Xaa at position 77 is Ile or Leu;

Xaa at position 79 is Lys, Gly, Asn, Met, Arg, Ile, or Gly;

Xaa at position 80 is Asn, Gly, Glu, or Arg;

Xaa at position 82 is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His, Met, Phe,Ser, Thr, Tyr or Val;

Xaa at position 87 is Leu or Ser;

Xaa at position 88 is Ala or Trp;

Xaa at position 91 is Ala or Pro;

Xaa at position 93 is Thr, Asp, or Ala;

Xaa at position 95 is His, Pro, Arg, Val, Gly, Asn, Ser or Thr;

Xaa at position 98 is His, Ile, Asn, Ala, Thr, Gln, Glu, Lys, Met, Ser,Tyr, Val or Leu;

Xaa at position 99 is Ile or Leu;

Xaa at position 100 is Lys or Arg;

Xaa at position 101 is Asp, Pro, Met, Lys, Thr, His, Pro, Asn, Ile, Leuor Tyr;

Xaa at position 105 is Asn, Pro, Ser, Ile or Asp;

Xaa at position 108 is Arg, Ala, or Ser;

Xaa at position 109 is Arg, Thr, Glu, Leu, or Ser;

Xaa at position 112 is Thr or Gln;

Xaa at position 116 is Lys, Val, Trp, Ala, His, Phe, Tyr or Ile;

Xaa at position 117 is Thr or Ser;

Xaa at position 120 is Asn, Pro, Leu, His, Val, or Gln;

Xaa at position 121 is Ala, Ser, Ile, Pro, or Asp;

Xaa at position 122 is Gln, Met, Trp, Phe, Pro, His, Ile, or Tyr;

Xaa at position 123 is Ala, Met, Glu, Ser, or Leu;

and which can additionally have Met- preceding the amino acid inposition 1; and wherein from 1 to 14 amino acids can be deleted from theN-terminus and/or from 1 to 15 amino acids can be deleted from theC-terminus; and wherein from 4 to 44 of the amino acids designated byXaa are different from the corresponding amino acids of native(1-133)human interleukin-3.

4. A composition of 3,wherein said human interleukin-3 mutantpolypeptide is of the Formula:

Xaa at position 42 is Gly, Asp, Ser, Ile, Leu, Met, Tyr, or Ala;

Xaa at position 45 is Gln, Val, Met or Asn;

Xaa at position 46 is Asp, Ser, Gln, His or Val;

Xaa at position 50 is Glu or Asp;

Xaa at position 51 is Asn, Pro or Thr;

Xaa at position 62 is Asn or Pro;

Xaa at position 76 is Ser, or Pro;

Xaa at position 82 is Leu, Trp, Asp, Asn Glu, His, Phe, Ser or Tyr;

Xaa at position 95 is His, Arg, Thr, Asn or Ser;

Xaa at position 98 is His, Ile, Leu, Ala, Gln, Lys, Met, Ser, Tyr orVal;

Xaa at position 100 is Lys or Arg;

Xaa at position 101 is Asp, Pro, His, Asn, Ile or Leu;

Xaa at position 105 is Asn, or Pro;

Xaa at position 108 is Arg, Ala, or Ser;

Xaa at position 116 is Lys, Val, Trp, Ala, His, Phe, or Tyr;

Xaa at position 121 is Ala, or Ile;

Xaa at position 122 is Gln, or Ile; and

Xaa at position 123 is Ala, Met or Glu.

5. A composition, comprising:

A human interleukin-3 mutant polypeptide of the Formula:

    Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                                       [SEQ ID NO:4]                              1               5                   10                  15                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa                                    20                  25                  30                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    35                  40                  45                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    50                  55                  60                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    65                  70                  75                   Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    80                  85                  90                   Xaa Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                    95                 100                 105                   Xaa Xaa Xaa Xaa Gln Gln                                                                       110                                                       

wherein

Xaa at position 3 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;

Xaa at position 4 is Asn, His, Leu, Ile, Phe, Arg, or Gln;

Xaa at position 5 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;

Xaa at position 6 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;

Xaa at position 7 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr,Ser or Val;

Xaa at position 8 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln, Leu,Val, or Gly;

Xaa at position 9 is Ile, Val, Ala, Leu, Gly, Trp, Lys, Phe, Leu, Ser,or Arg;

Xaa at position 10 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;

Xaa at position 11 is Thr, His, Gly, Gln, Arg, Pro, or Ala;

Xaa at position 12 is His, Thr, Phe, Gly, Arg, Ala, or Trp;

Xaa at position 13 is Leu, Gly, Arg, Thr, Ser, or Ala;

Xaa at position 14 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;

Xaa at position 15 is Gln, Asn, Leu, Pro, Arg, or Val;

Xaa at position 16 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;

Xaa at position 17 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;

Xaa at position 18 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;

Xaa at position 19 is Pro, Leu, Gln, Ala, Thr, or Glu;

Xaa at position 20 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr, Arg, Ala,Phe, Ile or Met;

Xaa at position 21 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;

Xaa at position 22 is Asp, Leu, or Val;

Xaa at position 23 is Phe, Ser, Pro, Trp, or Ile;

Xaa at position 24 is Asn, or Ala;

Xaa at position 26 is Leu, Trp, or Arg;

Xaa at position 27 is Asn, Cys, Arg, Leu, His, Met, Pro;

Xaa at position 28 is Gly, Asp, Ser, Cys, Ala, Lys, Asn, Thr, Leu, Val,Glu, Phe, Tyr, Ile or Met;

Xaa at position 29 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg,Thr, Gly or Ser;

Xaa at position 30 is Asp, Ser, Leu, Arg, Lys, Thr,Met, Trp, Glu, Asn,Gln, Ala or Pro;

Xaa at position 31 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, Asp, Asn,Arg, Ser, Ala, Ile, Glu, His or Trp;

Xaa at position 32 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly;

Xaa at position 33 is Ile, Gly, Val, Ser, Arg, Pro, or His;

Xaa at position 34 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr,Ala, Met, Val or Asn;

Xaa at position 35 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;

Xaa at position 36 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile,Val, His, Phe, Met or Gln;

Xaa at position 37 is Asn, Arg, Met, Pro, Ser, Thr, or His;

Xaa at position 38 is Asn, His, Arg, Leu, Gly, Ser, or Thr;

Xaa at position 39 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, Met, or;

Xaa at position 40 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His,Ala or Leu;

Xaa at position 41 is Arg, Thr, Val, Ser, Leu, or Gly;

Xaa at position 42 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His, Thr, Ala,Tyr, Phe, Leu, Val or Lys;

Xaa at position 43 is Asn or Gly;

Xaa at position 44 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

Xaa at position 45 is Glu Tyr, His, Leu, Pro, or Arg;

Xaa at position 46 is Ala, Ser, Pro, Tyr, Asn, or Thr;

Xaa at position 47 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;

Xaa at position 48 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;

Xaa at position 49 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;

Xaa at position 50 is Ala, Asn, Pro, Ser, or Lys;

Xaa at position 51 is Val, Thr, Pro, His, Leu, Phe, or Ser;

Xaa at position 52 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;

Xaa at position 53 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;

Xaa at position 54 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;

Xaa at position 55 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;

Xaa at position 56 is Asn, Leu, Val, Trp, Pro, or Ala;

Xaa at position 57 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, orAsn;

Xaa at position 58 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;

Xaa at position 59 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;

Xaa at position 60 is Ile, Met, Thr, Pro, Arg, Gly, Ala;

Xaa at position 61 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gln, orLeu;

Xaa at position 62 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

Xaa at position 63 is Ile, Ser, Arg, Thr, or Leu;

Xaa at position 64 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;

Xaa at position 65 is Lys, Thr, Gly, Asn, Met, Arg, Ile, or Asp;

Xaa at position 66 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;

Xaa at position 67 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;

Xaa at position 68 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr,Ser, Ala, Tyr, Phe, Ile, Met or Val;

Xaa at position 69 is Pro, Ala, Thr, Trp, Arg, or Met;

Xaa at position 70 is Cys, Glu, Gly, Arg, Met, or Val;

Xaa at position 71 is Leu, Asn, Val, or Gln;

Xaa at position 72 is Pro, Cys, Arg, Ala, or Lys;

Xaa at position 73 is Leu, Ser, Trp, or Gly;

Xaa at position 74 is Ala, Lys, Arg, Val, or Trp;

Xaa at position 75 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;

Xaa at position 76 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;

Xaa at position 77 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;

Xaa at position 78 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile orLeu;

Xaa at position 79 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;

Xaa at position 80 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His, Alaor Pro;

Xaa at position 81 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys,Ser, Ala, Trp, Phe, Ile or Tyr;

Xaa at position 82 is Pro, Lys, Tyr, Gly, Ile, or Thr;

Xaa at position 83 is Ile, Val, Lys, Ala, or Asn;

Xaa at position 84 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser,Phe, Met, Val, Lys, Arg, Tyr or Pro;

Xaa at position 85 is Ile, Leu, Arg, Asp, Val, Pro, Gln, Gly, Ser, Phe,or His;

Xaa at position 86 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, Pro;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn,Ser, Ala, Gly, Ile, Leu or Gln;

Xaa at position 88 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;

Xaa at position 89 is Asp, or Ser;

Xaa at position 90 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly;

Xaa at position 91 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys,Ile, Asp, or His;

Xaa at position 92 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;

Xaa at position 94 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser, Ala,or Pro;

Xaa at position 95 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;

Xaa at position 96 is Lys, Asn, Thr, Leu, Gln, Arg, His, Glu, Ser, Alaor Trp;

Xaa at position 97 is Leu, Ile, Arg, Asp, or Met;

Xaa at position 98 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;

Xaa at position 99 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu,Ile, Val or Asn;

Xaa at position 100 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;

Xaa at position 101 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, orMet;

Xaa at position 102 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp,Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;

Xaa at position 103 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;

Xaa at position 104 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;

Xaa at position 105 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;

Xaa at position 106 is Asn, Ala, Pro, Leu, His, Val, or Gln;

Xaa at position 107 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;

Xaa at position 108 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,or Cys;

Xaa at position 109 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;

and which can additionally have Met- or Met-Ala- preceding the aminoacid in position 1; and wherein from 4 to 44 of the amino acidsdesignated by Xaa are different from the corresponding native aminoacids of (1-133) human interleukin-3;

A colony stimulating factor selected from the group consisting ofGM-CSF, CSF-1, G-CSF, Meg-CSF (more recently referred to as c-mplligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3/flk2, humangrowth hormone, B-cell growth factor, B-cell differentiation factor,eosinophil differentiation factor and stem cell factor (SCF); and

At least one non-toxic pharmaceutically acceptable carrier.

6. A composition of 5, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

    Asn Cys Xaa Xaa Xaa Ile Xaa Glu Xaa Xaa Xaa Xaa Leu Lys Xaa                                                       [SEQ ID NO:5]                             1               5                   10                  15                    Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Asn Leu Asn Xaa Glu Xaa                                    20                  25                  30                   Xaa Xaa Ile Leu Met Xaa Xaa Asn Leu Xaa Xaa Xaa Asn Leu Glu                                    35                  40                  45                   Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Ile                                    50                  55                  60                   Glu Xaa Xaa Leu Xaa Xaa Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Thr                                    65                  70                  75                   Ala Xaa Pro Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa                                    80                  85                  90                   Xaa Xaa Phe Xaa Xaa Lys Leu Xaa Phe Xaa Xaa Xaa Xaa Leu Glu                                    95                 100                 105                   Xaa Xaa Xaa Xaa Gln Gln                                                                       110                                                       

wherein

Xaa at position 3 is Ser, Gly, Asp, Met, or Gln;

Xaa at position 4 is Asn, His, or Ile;

Xaa at position 5 is Met or Ile;

Xaa at position 7 is Asp or Glu;

Xaa at position 9 is Ile, Ala, Leu, or Gly;

Xaa at position 10 is Ile, Val, or Leu;

Xaa at position 11 is Thr, His, Gln, or Ala;

Xaa at position 12 is His or Ala;

Xaa at position 15 is Gln, Asn, or Val;

Xaa at position 16 is Pro, Gly, or Gln;

Xaa at position 17 is Pro, Asp, Gly, or Gln;

Xaa at position 18 is Leu, Arg, Gln, Asn, Gly, Ala, or Glu;

Xaa at position 19 is Pro or Glu;

Xaa at position 20 is Leu, Val, Gly, Ser, Lys, Ala, Arg, Gln, Glu, Ile,Phe, Thr or Met;

Xaa at position 21 is Leu, Ala, Asn, Pro, Gln, or Val;

Xaa at position 23 is Phe, Ser, Pro, or Trp;

Xaa at position 24 is Asn or Ala;

Xaa at position 28 is Gly, Asp, Ser, Cys, Ala, Asn, Ile, Leu, Met Tyr orArg;

Xaa at position 30 is Asp or Glu;

Xaa at position 31 is Gln, Val, Met, Leu, Thr, Ala, Asn, Glu, Ser orLys;

Xaa at position 32 is Asp, Phe, Ser, Thr, Ala, Asn, Gln, Glu, His, Ile,Lys, Tyr, Val or Cys;

Xaa at position 36 is Glu, Ala, Asn, Ser or Asp;

Xaa at position 37 is Asn, Arg, Met, Pro, Ser, Thr, or His;

Xaa at position 40 is Arg or Ala;

Xaa at position 41 is Arg, Thr, Val, Leu, or Gly;

Xaa at position 42 is Pro, Gly, Ser, Gln, Ala, Arg, Asn, Glu, Leu, Thr,Val or Lys;

Xaa at position 46 is Ala or Ser;

Xaa at position 48 is Asn, Pro, Thr, or Ile;

Xaa at position 49 is Arg or Lys;

Xaa at position 50 is Ala or Asn;

Xaa at position 51 is Val or Thr;

Xaa at position 52 is Lys or Arg;

Xaa at position 53 is Ser, Phe, or His;

Xaa at position 54 is Leu, Ile, Phe, or His;

Xaa at position 55 is Gln, Ala, Pro, Thr, Glu, Arg, or Gly;

Xaa at position 57 is Ala, Pro, or Arg;

Xaa at position 58 is Ser, Glu, Arg, or Asp;

Xaa at position 59 is Ala or Leu;

Xaa at position 62 is Ser, Val, Ala, Asn, Glu, Pro, or Gly;

Xaa at position 63 is Ile or Leu;

Xaa at position 65 is Lys, Thr, Gly, Asn, Met, Arg, Ile, Gly, or Asp;

Xaa at position 66 is Asn, Gly, Glu, or Arg;

Xaa at position 68 is Leu, Gln, Trp, Arg, Asp, Ala, Asn, Glu, His, Ile,Met, Phe, Ser, Thr, Tyr or Val;

Xaa at position 69 is Pro or Thr;

Xaa at position 71 is Leu or Val;

Xaa at position 73 is Leu or Ser;

Xaa at position 74 is Ala or Trp;

Xaa at position 77 is Ala or Pro;

Xaa at position 79 is Thr, Asp, Ser, Pro, Ala, Leu, or Arg;

Xaa at position 81 is His, Pro, Arg, Val, Leu, Gly, Asn, Phe, Ser orThr;

Xaa at position 82 is Pro or Tyr;

Xaa at position 83 is Ile or Val;

Xaa at position 84 is His, Ile, Asn, Leu, Ala, Thr, Leu, Arg, Gln, Leu,Lys, Met, Ser, Tyr, Val or Pro;

Xaa at position 85 is Ile, Leu, or Val;

Xaa at position 86 is Lys, Arg, Ile, Gln, Pro, or Ser;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Thr, Asn, Ile, Leu orTyr;

Xaa at position 90 is Trp or Leu;

Xaa at position 91 is Asn, Pro, Ala, Ser, Trp, Gln, Tyr, Leu, Lys, Ile,Asp, or His;

Xaa at position 92 is Glu, or Gly;

Xaa at position 94 is Arg, Ala, or Ser;

Xaa at position 95 is Arg, Thr, Glu, Leu, or Ser;

Xaa at position 98 is Thr, Val, or Gln;

Xaa at position 100 is Tyr or Trp;

Xaa at position 101 is Leu or Ala;

Xaa at position 102 is Lys, Thr, Val, Trp, Ser, Ala, His, Met, Phe, Tyror Ile;

Xaa at position 103 is Thr or Ser;

Xaa at position 106 is Asn, Pro, Leu, His, Val, or Gln;

Xaa at position 107 is Ala, Ser, Ile, Asn, Pro, Asp, or Gly;

Xaa at position 108 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,or Cys;

Xaa at position 109 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;

which can additionally have Met- or Met-Ala- preceding the amino acid inposition 1; and wherein from 4 to 35 of the amino acids designated byxaa are different from the corresponding amino acids of native humaninterleukin-3.

7. A composition of 6, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

    Asn Cys Xaa Xaa Met Ile Asp Glu Xaa Ile Xaa Xaa Leu Lys Xaa                                                       [SEQ ID NO:6]                              1               5                   10                  15                   Xaa Pro Xaa Pro Xaa Xaa Asp Phe Xaa Asn Leu Asn Xaa Glu Asp                                    20                  25                  30                   Xaa Xaa Ile Leu Met Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Glu                                    35                  40                  45                   Ala Phe Xaa Arg Xaa Xaa Lys Xaa Xaa Xaa Asn Ala Ser Ala Ile                                    50                  55                  60                   Glu Xaa Xaa Leu Xaa Xaa Leu Xaa Pro Cys Leu Pro Xaa Xaa Thr                                    65                  70                  75                   Ala Xaa Pro Xaa Arg Xaa Pro Ile Xaa Xaa Xaa Xaa Gly Asp Trp                                    80                  85                  90                   Xaa Glu Phe Xaa Xaa Lys Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu                                    95                 100                 105                   Xaa Xaa Xaa Xaa Gln Gln                                                                       110                                                       

wherein

Xaa at position 3 is Ser, Gly, Asp, or Gln;

Xaa at position 4 is Asn, His, or Ile;

Xaa at position 9 is Ile, Ala, Leu, or Gly;

Xaa at position 11 is Thr, His, or Gln;

Xaa at position 12 is His or Ala;

Xaa at position 15 is Gln or Asn;

Xaa at position 16 is Pro or Gly;

Xaa at position 18 is Leu, Arg, Asn, or Ala;

Xaa at position 20 is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile, Phe, Thror Met;

Xaa at position 21 is Leu, Ala, Asn, or Pro;

Xaa at position 24 is Asn or Ala;

Xaa at position 28 is Gly, Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr orArg;

Xaa at position 31 is Gln, Val, Met, Leu, Ala, Asn, Glu or Lys;

Xaa at position 32 is Asp, Phe, Ser, Ala, Gln, Glu, His, Val or Thr;

Xaa at position 36 is Glu, Asn, Ser or Asp;

Xaa at position 37 is Asn, Arg, Pro, Thr, or His;

Xaa at position 41 is Arg, Leu, or Gly;

Xaa at position 42 is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln;

Xaa at position 48 is Asn, Pro, or Thr;

Xaa at position 50 is Ala or Asn;

Xaa at position 51 is Val or Thr;

Xaa at position 53 is Ser or Phe;

Xaa at position 54 is Leu or Phe;

Xaa at position 55 is Gln, Ala, Glu, or Arg;

Xaa at position 62 is Ser, Val, Asn, Pro, or Gly;

Xaa at position 63 is Ile or Leu;

Xaa at position 65 is Lys, Asn, Met, Arg, Ile, or Gly;

Xaa at position 66 is Asn, Gly, Glu, or Arg;

Xaa at position 68 is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His, Met, Phe,Ser, Thr, Tyr or Val;

Xaa at position 73 is Leu or Ser;

Xaa at position 74 is Ala or Trp;

Xaa at position 77 is Ala or Pro;

Xaa at position 79 is Thr, Asp, or Ala;

Xaa at position 81 is His, Pro, Arg, Val, Gly, Asn, Ser or Thr;

Xaa at position 84 is His, Ile, Asn, Ala, Thr, Arg, Gln, Glu, Lys, Met,Ser, Tyr, Val or Leu;

Xaa at position 85 is Ile or Leu;

Xaa at position 86 is Lys or Arg;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Pro, Asn, Ile, Leu orTyr;

Xaa at position 91 is Asn, Pro, Ser, Ile or Asp;

Xaa at position 94 is Arg, Ala, or Ser;

Xaa at position 95 is Arg, Thr, Glu, Leu, or Ser;

Xaa at position 98 is Thr or Gln;

Xaa at position 102 is Lys, Val, Trp, or Ile;

Xaa at position 103 is Thr, Ala, His, Phe, Tyr or Ser;

Xaa at position 106 is Asn, Pro, Leu, His, Val, or Gln;

Xaa at position 107 is Ala, Ser, Ile, Pro, or Asp;

Xaa at position 108 is Gln, Met, Trp, Phe, Pro, His, Ile, or Tyr;

Xaa at position 109 is Ala, Met, Glu, Ser, or Leu;

and which can additionally have Met- or Met-Ala- preceding the aminoacid in position 1; and wherein from 4 to 26 of the amino acidsdesignated by Xaa are different from the corresponding amino acids ofnative (1-133)human interleukin-3.

8. The composition of 7, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

Xaa at position 17 is Ser, Lys, Asp, Met, Gln, or Arg;

Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;

Xaa at position 19 is Met, Arg, Gly, Ala, or Cys;

Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;

Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, or Val;

Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, or Gly;

Xaa at position 23 is Ile, Ala, Gly, Trp, Lys, Leu, Ser, or Arg;

Xaa at position 24 is Ile, Gly, Arg, or Ser;

Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;

Xaa at position 26 is His, Thr, Phe, Gly, Ala, or Trp;

Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;

Xaa at position 28 is Lys, Leu, Gln, Gly, Pro, Val or Trp;

Xaa at position 29 is Gln, Asn, Pro, Arg, or Val;

Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;

Xaa at position 31 is Pro, Asp, Gly, Arg, Leu, or Gln;

Xaa at position 32 is Leu, Arg, Gln, Asn, Gly, Ala, or Glu;

Xaa at position 33 is Pro, Leu, Gln, Thr, or Glu;

Xaa at position 34 is Leu, Gly, Ser, or Lys;

Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, or Gln;

Xaa at position 36 is Asp, Leu, or Val;

Xaa at position 37 is Phe, Ser, or Pro;

Xaa at position 38 is Asn, or Ala;

Xaa at position 40 is Leu, Trp, or Arg;

Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, Pro;

Xaa at position 42 is Gly, Asp, Ser, Cys, or Ala;

Xaa at position 42 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, or Ser;

Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, or Pro;

Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, or Trp;

Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, or Gly;

Xaa at position 47 is Ile, Gly, Ser, Arg, Pro, or His;

Xaa at position 48 is Leu, Ser, Cys, Arg, His, Phe, or Asn;

Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;

Xaa at position 50 is Glu, Leu, Thr, Asp, or Tyr;

Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;

Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;

Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or;

Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, or Leu;

Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;

Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, or Lys;

Xaa at position 57 is Asn or Gly;

Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;

Xaa at position 60 is Ala, Ser, Tyr, Asn, or Thr;

Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;

Xaa at position 62 is Asn His, Val, Arg, Pro, Thr, or Ile;

Xaa at position 63 is Arg, Tyr, Trp, Ser, Pro, or Val;

Xaa at position 64 is Ala, Asn, Ser, or Lys;

Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;

Xaa at position 66 is Lys, Ile, Val, Asn, Glu, or Ser;

Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;

Xaa at position 68 is Leu, Val, Trp, Ser, Thr, or His;

Xaa at position 69 is Gln, Ala, Pro, Thr, Arg, Trp, Gly, or Leu;

Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;

Xaa at position 71 is Ala, Met, Leu, Arg, Glu, Thr, Gln, Trp, or Asn;

Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;

Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;

Xaa at position 74 is Ile, Thr, Pro, Arg, Gly, Ala;

Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, or Leu;

Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

Xaa at position 77 is Ile, Ser, Arg, or Thr;

Xaa at position 78 is Leu, Ala, Ser, Glu, Gly, or Arg;

Xaa at position 79 is Lys, Thr, Gly, Asn, Met, Ile, or Asp;

Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, or Arg;

Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, or Lys;

Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, or Asp;

Xaa at position 83 is Pro, Thr, Trp, Arg, or Met;

Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;

Xaa at position 85 is Leu, Asn, or Gln;

Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;

Xaa at position 87 is Leu, Ser, Trp, or Gly;

Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;

Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, or Asn;

Xaa at position 90 is Ala, Ser, Asp, Ile, or Met;

Xaa at position 91 is Ala, Ser, Thr, Phe, Leu, Asp, or His;

Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, or Leu;

Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;

Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, or Pro;

Xaa at position 95 is His, Gln, Pro, Val, Leu, Thr or Tyr;

Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;

Xaa at position 97 is Ile, Lys, Ala, or Asn;

Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, or Pro;

Xaa at position 99 is Ile, Arg, Asp, Pro, Gln, Gly, Phe, or His;

Xaa at position 100 is Lys, Tyr, Leu, His, Ile, Ser, Gln, or Pro;

Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tlyr, or Gln;

Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;

Xaa at position 103 is Asp, or Ser;

Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly;

Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys,Ile, or His;

Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;

Xaa at position 108 is Arg, Asp, Leu, Thr, Ile, or Pro;

Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly.

9. A composition of 8, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

    [SEQ ID NO:7]                                                                        1               5                   10                                 (Met).sub.m -Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr                                  15                  20                                            Ser Trp Val Asn Cys Ser Xaa Xaa Xaa Asp Glu Ile Ile                           25                  30                  35                                    Xaa His Leu Lys Xaa Pro Pro Xaa Pro Xaa Leu Asp Xaa                                   40                  45              50                                Xaa Asn Leu Asn Xaa Glu Asp Xaa Asp Ile Leu Xaa Glu                                            55                 60                                        Xaa Asn Leu Arg Xaa Xaa Asn Leu Xaa Xaa Phe Xaa Xaa                               65                  70               75                                   Ala Xaa Lys Xaa Leu Xaa Asn Ala Ser Xaa Ile Glu Xaa                                       80                  85                                            Ile Leu Xaa Asn Leu Xaa Pro Cys Xaa Pro Xaa Xaa Thr                           90                  95                  100                                   Ala Xaa Pro Xaa Arg Xaa Pro Ile Xaa Ile Xaa Xaa Gly                                   105                 110                 115                           Asp Trp Xaa Glu Phe Arg Xaa Lys Leu Xaa Phe Tyr Leu                                           120                 125                                       Xaa Xaa Leu Glu Xaa Ala Gln Xaa Gln Gln Thr Thr Leu                               130                                                                       Ser Leu Ala Ile Phe                                                       

wherein m is 0 or 1; Xaa at position 18 is Asn or Ile; Xaa at position19 is Met, Ala or Ile; Xaa at position 20 is Ile, Pro or Ile; Xaa atposition 23 is Ile, Ala or Leu; Xaa at position 25 is Thr or His; Xaa atposition 29 is Gln, Arg, Val or Ile; Xaa at position 32 is Leu, Ala, Asnor Arg; Xaa at position 34 is Leu or Ser; Xaa at position 37 is Phe,Pro, or Ser; Xaa at position 38 is Asn or Ala; Xaa at position 42 isGly, Ala, Ser, Asp or Asn; Xaa at position 45 is Gln, Val, or Met; Xaaat position 46 is Asp or Ser; Xaa at position 49 is Met, Ile, Leu orAsp; Xaa at position 50 is Glu or Asp; Xaa at position 51 is Asn Arg orSer; Xaa at position 55 is Arg, Leu, or Thr; Xaa at position 56 is Proor Ser; Xaa at position 59 is Glu or Leu; Xaa at position 60 is Ala orSer; Xaa at position 62 is Asn, Val or Pro; Xaa at position 63 is Arg orHis; Xaa at position 65 is Val or Ser; Xaa at position 67 is Ser, Asn,His or Gln; Xaa at position 69 is Gln or Glu; Xaa at position 73 is Alaor Gly; Xaa at position 76 is Ser, Ala or Pro; Xaa at position 79 isLys, Arg or Ser; Xaa at position 82 is Leu, Glu, Val or Trp; Xaa atposition 85 is Leu or Val; Xaa at position 87 is Leu, Ser, Tyr; Xaa atposition 88 is Ala or Trp; Xaa at position 91 is Ala or Pro; Xaa atposition 93 is Pro or Ser; Xaa at position 95 is His or Thr; Xaa atposition 98 is His, Ile, or Thr; Xaa at position 100 is Lys or Arg; Xaaat position 101 is Asp, Ala or Met; Xaa at position 105 is Asn or Glu;Xaa at position 109 is Arg, Glu or Leu; Xaa at position 112 is Thr orGln; Xaa at position 116 is Lys, Val, Trp or Ser; Xaa at position 117 isThr or Ser; Xaa at position 120 is Asn, Gln, or His; Xaa at position 123is Ala or Glu; with the proviso that from four to forty-four of theamino acids designated by Xaa are different from the corresponding aminoacids of native human interleukin-3.

10. The composition of 9, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

                1               5               10                                (Met.sub.m -Ala.sub.n).sub.p -Asn Cys Ser Xaa Xaa Xaa Asp Glu Xaa                                             [SEQ ID NO:8]                                                 15                  20                                        Xaa His Leu Lys Xaa Pro Pro Xaa Pro Xaa Leu Asp Xaa                               25                  30                  35                                Xaa Asn Leu Asn Xaa Glu Asp Xaa Xaa Ile Leu Xaa Glu                                       40                  45                                            Xaa Asn Leu Arg Xaa Xaa Asn Leu Xaa Xaa Phe Xaa Xaa                           50                  55                  60                                    Ala Xaa Lys Xaa Leu Xaa Asn Ala Ser Xaa Ile Glu Xaa                                   65                  70                  75                            Ile Leu Xaa Asn Xaa Xaa Pro Cys Xaa Pro Xaa Ala Thr                                           80                  85                                        Ala Xaa Pro Xaa Arg Xaa pro Ile Xaa Ile Xaa Xaa Gly                                90                 95                  100                               Asp Trp Xaa Glu Phe Arg Xaa Lys Leu Xaa Phe Tyr Leu                                       105                 110                                           Xaa Xaa Leu Glu Xaa Ala Gln Xaa Gln Gln                                   

wherein m is 0 or 1; n is 0 or 1; p is 0 or 1; Xaa at position 4 is Asnor Ile; Xaa at position 5 is Met, Ala or Ile: Xaa at position 6 is Ile,Pro or Leu; Xaa at position 9 is Ile, Ala or Leu; Xaa at position 11 isThr or His; Xaa at position 15 is Gln, Arg, Val or Ile; xaa at position18 is Leu, Ala, Asn or Arg; Xaa at position 20 is Leu or Ser; Xaa atposition 23 is Phe, Pro, or Ser; Xaa at position 24 is Asn or Ala; Xaaat position 28 is Gly, Ala, Ser, Asp or Asn; Xaa at position 31 is Gln,Val, or Met; Xaa at position 32 is Asp or Ser; Xaa at position 35 isMet, Ile or Asp; Xaa at position 36 is Glu or Asp; Xaa at position 37 isAsn, Arg or Ser; Xaa at position 41 is Arg, Leu, or Thr; Xaa at position42 is Pro or Ser; Xaa at position 45 is Glu or Leu; Xaa at position 46is Ala or Ser; Xaa at position 48 is Asn, Val or Pro; Xaa at position 49is Arg or His; Xaa at position 51 is Val or Ser; Xaa at position 53 isSer, Asn, His or Gln; Xaa at position 55 is Gln or Glu; Xaa at position59 is Ala or Gly; Xaa at position 62 is Ser, Ala or Pro; Xaa at position65 is Lys, Arg or Ser; Xaa at position 67 is Leu, Glu, or Val; Xaa atposition 68 is Leu, Glu, Val or Trp; Xaa at position 71 is Leu or Val;Xaa at position 73 is Leu, Ser or Tyr; Xaa at position 74 is Ala or Trp;Xaa at position 77 is Ala or Pro; Xaa at position 79 is Pro or Ser; Xaaat position 81 is His or Thr; Xaa at position 84 is His, Ile, or Thr;Xaa at position 86 is Lys or Arg; Xaa at position 87 is Asp, Ala or Met;Xaa at position 91 is Asn or Glu; Xaa at position 95 is Arg, Glu, Leu;Xaa at position 98 Thr or Gln; Xaa at position 102 is Lys, Val, Trp orSer; Xaa at position 103 is Thr or Ser; xaa at position 106 is Asn, Gln,or His; Xaa at position 109 is Ala or Glu; with the proviso that fromfour to forty-four of the amino acids designated by Xaa are differentfrom the corresponding amino acids of native (15-125)humaninterleukin-3.

11. The composition of 10, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro AlaPro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:9];

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro AsnPro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:10];

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val Pro Pro AlaPro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:11];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluArg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys Asn LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:12];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluArg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:13];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluArg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:14];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu ProSer Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp TrpGln Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:15];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro Cys Leu ProSer Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala Gly Asp TrpGln Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:16];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala GlnGlu Gln Gln [SEQ ID NO:17];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu His Ala GlnGlu Gln Gln [SEQ ID NO:18];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu ProSer Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp TrpGln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala GlnGlu Gln Gln [SEQ ID NO:19];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro Cys Leu ProSer Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala Gly Asp TrpGln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala GlnGlu Gln Gln [SEQ ID NO:20];

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln Pro Pro LeuPro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile Leu Met GluAsn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val Lys Ser LeuGln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro Cys Leu ProSer Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala Gly Asp TrpGln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu His Ala GlnGlu Gln Gln [SEQ ID NO:21];

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro AlaPro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met GluArg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:22];

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro AsnPro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met GluArg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:23];

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val Pro Pro AlaPro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met GluArg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys Asn LeuGlu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro Cys Leu ProLeu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp Gly Asp TrpAsn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala GlnAla Gln Gln [SEQ ID NO:24];

Met Ala Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln ProPro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile LeuMet Glu Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val LysSer Leu Gln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:25];

Met Ala Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln ProPro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile LeuMet Glu Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val LysSer Leu Gln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:26];

Met Ala Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys Gln ProPro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp Gln Asp Ile LeuMet Glu Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala Phe Asn Arg Ala Val LysSer Leu Gln Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu HisAla Gln Glu Gln Gln [SEQ ID NO:27];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro CysLeu Pro Leu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp GlyAsp Trp Asn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu AsnAla Gln Ala Gln Gln [SEQ ID NO:28];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro CysLeu Pro Leu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp GlyAsp Trp Asn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu AsnAla Gln Ala Gln Gln [SEQ ID NO:29];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val ProPro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Ala Ile Glu Ser Ile Leu Lys Asn Leu Leu Pro CysLeu Pro Leu Ala Thr Ala Ala Pro Thr Arg His Pro Ile His Ile Lys Asp GlyAsp Trp Asn Glu Phe Arg Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu AsnAla Gln Ala Gln Gln [SEQ ID NO:30];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:31];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:32];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val ProPro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:33];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:34];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val ProPro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:35];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu HisAla Gln Glu Gln Gln [SEQ ID NO:36];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val ProPro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu HisAla Gln Glu Gln Gln [SEQ ID NO:37];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:38];

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Val Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Thr Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Glu HisAla Gln Glu Gln Gln [SEQ ID NO:39].

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Asp Arg Asn Leu Arg Leu Ser Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:40]

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ala Ile His His Leu Lys Arg ProPro Ala Pro Ser Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Met Ser Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:41]

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His HiS Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Met Ser Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:42]

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile LeuMet Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:43]

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:44]

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Met Ser Ile LeuMet Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val LysAsn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:45]

Met Ala Tyr Pro Glu Thr Asp Tyr Lys Asp Asp Asp Asp Lys Asn Cys Ser IleMet Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu AspPro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met Glu Arg Asn Leu ArgLeu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala SerGly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr AlaAla Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe ArgGlu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln [SEQID NO:46]

Met Ala Tyr Pro Glu Thr Asp Tyr Lys Asp Asp Asp Asp Lys Asn Cys Ser IleMet Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Asn Pro Leu Leu AspPro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met Glu Arg Asn Leu ArgThr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala SerGly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr AlaAla Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe ArgGlu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln [SEQID NO:47] and

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Leu Ile His His Leu Lys Ile ProPro Asn Pro Ser Leu Asp Ser Ala Asn Leu Asn Ser Glu Asp Val Ser Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID No:48].

12. The composition of claim 11, wherein said human interleukin-3 mutantpolypeptide is of the Formula:

Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ProPro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile LeuMet Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val LysHis Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro CysLeu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala GlyAsp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu GlnAla Gln Glu Gln Gln [SEQ ID NO:32].

Also included in the present invention is a method of increasingmulti-lineage hematopoietic cell production in a mammal in need thereofcomprising administering a pharmaceutically effective amount of a humaninterleukin-3 mutant polypeptide as disclosed above with CSF preferablyG-CSF or GM-CSF more preferably G-CSF simultaneously as a composition orone after the other.

Materials and Methods for IL-3 Variant Expression in E. coli

Unless noted otherwise, all specialty chemicals were obtained from SigmaCo., (St. Louis, Mo.). Restriction endonucleases, T4 poly-nucleotideskinase, E. coli DNA polymerase I large fragment (Klenow) and T4 DNAligase were obtained from New England Biolabs (Beverly, Mass.).

Escherichia coli Strains

Strain JM101: delta (pro lac), supE, thi, F' (traD36, rpoAB, lacI-Q,lacZdeltaM15) (Messing, 1979). This strain can be obtained from theAmerican Type Culture Collection (ATCC), 12301 Parklawn Drive,Rockville, Md. 20852, accession number 33876. MON105 (W3110 rpoH358) isa derivative of W3110 (Bachmann, 1972) and has been assigned ATCCaccession number 55204. Strain GM48: dam-3, dcm-6, gal, ara, lac, thr,leu, tonA, tsx (Marinus, 1973) was used to make plasmid DNA that is notmethylated at the sequence GATC.

Genes and Plasmids

The gene used for hIL-3 production in E. coli was obtained from BritishBiotechnology Incorporated, Cambridge, England, catalogue number BBG14.This gene is carried on a pUC based plasmid designated pP0518. Manyother human CSF genes can be obtained from R&D Systems, Inc. (Minn,Minn.) including IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-7,IL-8, G-CSF, GM-CSF and LIF.

The plasmids used for production of hIL-3 in E. coli contain geneticelements whose use has been described (olins et al., 1988; olins andRangwala, 1990). The replicon used is that of pBR327 (Covarrubias, etal., 1981) which is maintained at a copy number of about 100 in the cell(Soberon et al., 1980). A gene encoding the beta-lactamase protein ispresent on the plasmids. This protein confers ampicillin resistance onthe cell. This resistance serves as a selectable phenotype for thepresence of the plasmid in the cell.

For cytoplasmic expression vectors the transcription promoter is derivedfrom the recA gene of E. coli (Sancar et al., 1980). This promoter,designated precA, includes the RNA polymerase binding site and the lexArepressor binding site (the operator). This segment of DNA provides highlevel transcription that is regulated even when the recA promoter is ona plasmid with the pBR327 origin of replication (Olins et al., 1988)incorporated herein by reference.

The ribosome binding site used is that from gene 10 of phage T7 (Olinset al., 1988). This is encoded in a 100 base pair (bp) fragment placedadjacent to precA. In the plasmids used herein, the recognition sequencefor the enzyme NcoI (CCATGG) follows the g10-L. It is at this NcoI sitethat the hIL-3 genes were joined to the plasmid. It is expected that thenucleotide sequence at this junction will be recognized in mRNA as afunctional start site for translation (Olins et al., 1988). The hIL-3genes used were engineered to have a HindIII recognition site (AAGCTT)downstream from the coding sequence of the gene. At this HindIII site isa 514 base pair RsaI fragment containing the origin of replication ofthe single stranded phage fl (Dente et al., 1983; Olins, et al., 1990)both incorporated herein by reference. A plasmid containing theseelements is pMON2341. Another plasmid containing these elements ispMON5847 which has been deposited at the American Type CultureCollection, 12301 Parklawn Drive, Rockville, Md. 20852 under theaccession number ATCC 68912.

In secretion expression plasmids the transcription promoter is derivedfrom the ara B, A, and D genes of E.coli (Greenfield et al., 1978). Thispromoter is designated pAraBAD and is contained on a 323 base pairSacII, BglII restriction fragment. The LamB secretion leader (Wong etal., 1988, Clement et al., 1981) is fused to the N-terminus of the hIL-3gene at the recognition sequence for the enzyme NcoI (5'CCATGG3'). ThehIL-3 genes used were engineered to have a HindIII recognition site(5'AAGCTT3') following the coding sequence of the gene.

Recombinant DNA Methods

Synthetic Gene Assembly

The hIL-3 variant genes and other CSF genes can be constructed by theassembly of synthetic oligonucleotides. Synthetic oligonucleotides weredesigned so that they would anneal in complementary pairs, withprotruding single stranded ends, and when the pairs were properlyassembled would result in a DNA sequence that encoded a portion of thedesired gene. Amino acid substitutions in the hIL-3 gene were made bydesigning the oligonucleotides to encode the desired substitutions. Thecomplementary oligonucleotides were annealed at concentration of 1picomole per microliter in ligation buffer plus 50 mM NaCl. The sampleswere heated in a 100 ml beaker of boiling water and permitted to coolslowly to room temperature. One picomole of each of the annealed pairsof oligonucleotides were ligated with approximately 0.2 picomoles ofplasmid DNA, digested with the appropriate restriction enzymes, inligation buffer (25 mM Tris pH 8.0, 10 mM MgCl₂, 10 mM dithiothreitol, 1mM ATP, 2 mM spermidine) with T4 DNA ligase obtained from New EnglandBiolabs (Beverly, Mass.) in a total volume of 20 μl at room temperatureovernight.

Polymerase Chain Reaction

Polymerase Chain Reaction (hereafter referred to as PCR) techniques(Saiki, 1985) used the reagent kit and thermal cycler from Perkin-ElmerCetus (Norwalk, Conn.). PCR is based on a thermostable DNA polymerasefrom Thermus aquaticus. The PCR technique is a DNA amplification methodthat mimics the natural DNA replication process in that the number ofDNA molecules doubles after each cycle, in a way similar to in vivoreplication. The DNA polymerase mediated extension is in a 5' to 3'direction. The term "primer" as used herein refers to an oligonucleotidesequence that provides an end to which the DNA polymerase can addnucleotides that were complementary to a nucleotide sequence. The latternucleotide sequence is referred to as the "template", to which theprimers were annealed. The amplified PCR product is defined as theregion comprised between the 5' ends of the extension primers. Since theprimers have defined sequences, the product will have discrete ends,corresponding to the primer sequences. The primer extension reaction iscarried out using 20 picomoles (pmoles) of each of the oligonucleotidesand 1 picogram of template plasmid DNA for 35 cycles (1 cycle is definedas 94 degrees C for one minute, 50 degrees C for two minutes and 72degrees for three minutes.). The reaction mixture was extracted with anequal volume of phenol/chloroform (50% phenol and 50% chloroform, volumeto volume) to remove proteins. The aqueous phase, containing theamplified DNA, and solvent phase were separated by centrifugation for 5minutes in a microcentrifuge (Model 5414 Eppendorf Inc, Fremont Calif.).To precipitate the amplified DNA the aqueous phase was removed andtransferred to a fresh tube to which was added 1/10 volume of 3M NaOAc(pH 5.2) and 2.5 volumes of ethanol (100% stored at minus 20 degrees C).The solution was mixed and placed on dry ice for 20 minutes. The DNA waspelleted by centrifugation for 10 minutes in a microcentrifuge and thesolution was removed from the pellet. The DNA pellet was washed with 70%ethanol, ethanol removed and dried in a speedvac concentrator (Savant,Farmingdale, N.Y.). The pellet was resuspended in 25 microliters of TE(20 mM Tris-HCl pH 7.9, 1 mM EDTA). Alternatively the DNA wasprecipitated by adding equal volume of 4M NH₄ OAc and one volume ofisopropanol [Treco et al., (1988)]. The solution was mixed and incubatedat room temperature for 10 minutes and centrifuged. These conditionsselectively precipitate DNA fragments larger than ˜20 bases and wereused to remove oligonucleotide primers. One quarter of the reaction wasdigested with restriction enzymes [Higuchi, (1989)] an on completionheated to 70 degrees C to inactivate the enzymes.

Recovery of Recombinant Plasmids from Ligation Mixes

E. coli JM101 cells were made competent to take up DNA. Typically, 20 to100 ml of cells were grown in LB medium to a density of approximately150 Klett units and then collected by centrifugation. The cells wereresuspended in one half culture volume of 50 mM CaCl₂ and held at 4° C.for one hour. The cells were again collected by centrifugation andresuspended in one tenth culture volume of 50 mM CaCl₂. DNA was added toa 150 microliter volume of these cells, and the samples were held at 4°C. for 30 minutes. The samples were shifted to 42° C. for one minute,one milliliter of LB was added, and the samples were shaken at 37° C.for one hour. Cells from these samples were spread on plates containingampicillin to select for transformants. The plates were incubatedovernight at 37° C. Single colonies were picked, grown in LBsupplemented with ampicillin overnight at 37° C. with shaking. Fromthese cultures DNA was isolated for restriction analysis.

Culture Medium

LB medium (Maniatis et al., 1982) was used for growth of cells for DNAisolation. M9 minimal medium supplemented with 1.0% casamino acids, acidhydrolyzed casein, Difco (Detroit, Michigan) was used for cultures inwhich recombinant IL-3 variant was produced. The ingredients in the M9medium were as follows: 3 g/liter KH₂ PO₄, 6 g/l Na₂ HPO₄, 0.5 g/l NaCl,1 g/l NH₄ Cl, 1.2 mM MgSO₄, 0.025 mM CaCl₂, 0.2% glucose (0.2% glycerolwith the AraBAD promoter), 1% casamino acids, 0.1 ml/l trace minerals(per liter 108 g FeCl₃.6H₂ O, 4.0 g ZnSO₄.7H₂ O, 7.0 COCl₂.2H₂ O, 7.0 gNa₂ MoO₄.2H₂ O, 8.0 g CuSO₄.5H₂ O, 2.0 g H₃ BO₃, 5.0 g MnSO₄.H₂ O, 100ml concentrated HCl). Bacto agar was used for solid media and ampicillinwas added to both liquid and solid LB media at 200 micrograms permilliliter.

Production of IL-3 Variants in E. coli with Vectors Employing the recAPromoter

E. coli strains harboring the plasmids of interest were grown at 37° C.in M9 plus casamino acids medium with shaking in a Gyrotory water bathModel G76 from New Brunswick Scientific (Edison, N.J.). Growth wasmonitored with a Klett Summerson meter (green 54 filter), Klett Mfg. Co.(New York, N.Y.). At a Klett value of approximately 150, an aliquot ofthe culture (usually one milliliter) was removed for protein analysis.To the remaining culture, nalidixic acid (10 mg/ml) in 0.1 N NaOH wasadded to a final concentration of 50 μg/ml. The cultures were shaken at37° C. for three to four hours after addition of nalidixic acid. A highdegree of aeration was maintained throughout the bacterial growth inorder to achieve maximal production of the desired gene product. Thecells were examined under a light microscope for the presence ofrefractile bodies (RBs). One milliliter aliquots of the culture wereremoved for analysis of protein content.

Extraction, Refolding and Purification of IL-3 Variant ProteinsExpressed as Refractile Bodies in E. coli

Extraction of refractile bodies (RB's):

For each gram of RB's (and typically one gram is obtained from a 300 mlE. coli culture), 5 ml of a solution containing 6M guanidinehydrochloride (GnHCl), 50 mM 2-N-cyclohexylaminoethanesulfonic acid(CHES) pH 9.5 and 20 mM dithiothreitol (DTT) was added. The RB's wereextracted with a Bio-Homogenizer for 15-30 seconds and gently rocked for2 hours at 5 degrees centigrade (5° C.) to allow the protein tocompletely reduce and denature.

Refolding of the IL-3 Muteins

The protein solution was transferred to dialysis tubing (1000 molecularweight cut-off) and dialyzed against at least 100 volumes of 4M GnHCl-50mM CHES pH 8.0. The dialysis was continued overnight at 5° C. whilegently stirring. Subsequently dialysis was continued against at least100 volumes of 2M GnHCl-50 mM CHES pH 8.0 and dialyzed overnight at 5°C. while gently stirring.

Purification of the IL-3 Muteins

The protein solution was removed from the dialysis tubing and acidifiedby the addition of 40% acetonitrile (CH₃ CN)--0.2% trifluoroacetic acid(TFA) to a final concentration of 20% CH₃ CN-0.1% TFA. This wascentrifuged (16,000×g for 5 minutes) to clarify and the supernatant wasloaded onto a Vydac C-18 reversed phase column (10×250 mm) availablefrom Vydac (Hesperia, Calif.) previously equilibrated in 20% CH₃ CN-0.1%TFA. The column was eluted with a linear gradient (0.2% CH₃ CN/minute)between 40-50% CH₃ CN-0.1% TFA at a flow rate of 3 ml/minute whilecollecting 1.5 ml fractions. The fractions were analyzed bypolyacrylamide gel electrophoresis (SDS-PAGE) and the appropriatefractions pooled. The pooled material was dried by lyophilization or ina Speed Vac concentrator. The dry powder was reconstituted with 10 mMammonium bicarbonate pH 7.5, centrifuged (16,000×g for 5 minutes) toclarify and assayed for protein concentration by the method of Bradford(1976) with bovine serum albumin as the standard. Such protein can befurther analyzed by additional techniques such as, SDS-PAGE,electrospray mass spectrometry, reverse phase HPLC, capillary zoneelectrophoresis, amino acid composition analysis, and ELISA(enzyme-linked immunosorbent assay).

hIL-3 SANDWICH ELISA

The IL-3 variant protein concentrations can be determined using asandwich ELISA based on an affinity purified polyclonal goatanti-rhIL-3. Microtiter plates (Dynatech Immulon II) were coated with150 μl goat-anti-rhIL-3 at a concentration of approximately 1 μg/ml in100 mM NaHCO₃, pH 8.2. Plates were incubated overnight at roomtemperature in a chamber maintaining 100% humidity. Wells were emptiedand the remaining reactive sites on the plate were blocked with 200 μlof solution containing 10 mM PBS, 3% BSA and 0.05% Tween 20, pH 7.4 for1 hour at 37° C. and 100% humidity. Wells were emptied and washed 4×with 150 mM NaCl containing 0.05% Tween 20 (wash buffer). Each well thenreceives 150 μl of dilution buffer (10 mM PBS containing 0.1% BSA, 0.01%Tween 20, pH 7.4), containing rhIL-3 standard, control, sample ordilution buffer alone. A standard curve was prepared with concentrationsranging from 0.125 ng/ml to 5 ng/ml using a stock solution of rhIL-3(concentration determined by amino acid composition analysis). Plateswere incubated 2.5 hours at 37° C. and 100% humidity. Wells were emptiedand each plate was washed 4× with wash buffer. Each well then received150 μl of an optimal dilution (as determined in a checkerboard assayformat) of goat anti-rhIL-3 conjugated to horseradish peroxidase. Plateswere incubated 1.5 hours at 37° C. and 100% humidity. Wells were emptiedand each plate was washed 4× with wash buffer. Each well then received150 μl of ABTS substrate solution (Kirkegaard and Perry). Plates wereincubated at room temperature until the color of the standard wellscontaining 5 ng/ml rhIL-3 had developed enough to yield an absorbancebetween 0.5-1.0 when read at a test wavelength of 410 nm and a referencewavelength of 570 nm on a Dynatech microtiter plate reader.Concentrations of immunoreactive rhIL-3 in unknown samples werecalculated from the standard curve using software supplied with theplate reader.

The following examples will illustrate the invention in greater detailalthough it will be understood that the invention is not limited tothese specific examples.

EXAMPLE 1 Isolation of 1-332 and 1-153 Amino Acid Forms of Meg-CSF

A. Reverse transcriptase reaction Meg-CSF (more recently known as c-mplligand) sequence based on Genbank accession #L33410). Human fetal liverA+ RNA was obtained from Clontech (Palo Alto, Calif.). The first strandcDNA reactions were carried out using a cDNA Cycle™ Kit obtained fromInvitrogen (San Diego, Calif.).

B. Polymerase Chain Reactions

Following the reverse transcriptase (RT) reaction, the 1-332 c-mplligand was amplified via PCR using the oligonucleotide primersc-mplBglII [SEQ ID NO:50] and c-mplEcoRI [SEQ ID NO:51]. Following theRT reaction, the 1-153 c-mpl ligand was amplified using theoligonucleotide primers c-mplNcoI [SEQ ID NO:52] and c-mplHindIII [SEQID NO:53].

EXAMPLE 2 BHK Expression Vector for Full Length c-mpl Ligand

The full length c-mpl ligand PCR product is digested with BglII andEcoRI restriction enzymes for transfer to a mammalian expression vector.The expression vector, pMON3976, is digested with BamHI and EcoRI, whichallows it to accept the BglII-EcoRI PCR fragments. pMON3976 is aderivative of pMoN3359 which is a pUC18-based vector containing amammalian expression cassette. The cassette, which includes a herpessimplex viral promoter IE110 (-800 to +120) and a SV40 latepoly-adenylation (poly-A) signal, was subcloned into the pUC18polylinker [Hippenmeyer et al., (1993)]. The original EcoRI site 5' tothe promoter was removed and a new EcoRI site added 3' to the BamHIsite. These unique restriction enzyme sites are located between thepromoter and poly-A signal to facilitate subcloning DNA fragments asBamHI-EcoRI or BglII-EcoRI fragments in a 5' to 3' direction fortranscription and translation. The resulting plasmid encodes thepolypeptide with the following amino acid sequence:

Met Glu Leu Thr Glu Leu Leu Leu Val Val Met Leu Leu Leu

Thr Ala Arg Leu Thr Leu Ser Ser Pro Ala Pro Pro Ala Cys

Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val

Leu His Ser Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu

Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly

Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln Asp Ile

Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala

Arg Gly Gln Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly

Gln Leu Ser Gly Gln Val Arg Leu Leu Leu Gly Ala Leu Gln

Ser Leu Leu Gly Thr Gln Leu Pro Pro Gln Gly Arg Thr Thr

Ala His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gln His

Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly

Ser Thr Leu Cys Val Arg Arg Ala Pro Pro Thr Thr Ala Val

Pro Ser Arg Thr Ser Leu Val Leu Thr Leu Asn Glu Leu Pro

Asn Arg Thr Ser Gly Leu Leu Glu Thr Asn Phe Thr Ala Ser

Ala Arg Thr Thr Gly Ser Gly Leu Leu Lys Trp Gln Gln Gly

Phe Arg Ala Lys Ile Pro Gly Leu Leu Asn Gln Thr Ser Arg

Ser Leu Asp Gln Ile Pro Gly Tyr Leu Asn Arg Ile His Glu

Leu Leu Asn Gly Thr Arg Gly Leu Phe Pro Gly Pro Ser Arg

Arg Thr Leu Gly Ala Pro Asp Ile Ser Ser Gly Thr Ser Asp

Thr Gly Ser Leu Pro Pro Asn Leu Gln Pro Gly Tyr Ser Pro

Ser Pro Thr His Pro Pro Thr Gly Gln Tyr Thr Leu Phe Pro

Leu Pro Pro Thr Leu Pro Thr Pro Val Val Gln Leu His Pro

Leu Leu Pro Asp Pro Ser Ala Pro Thr Pro Thr Pro Thr Ser

Pro Leu Leu Asn Thr Ser Tyr Thr His Ser Gln Asn Leu Ser

Gln Glu Gly [SEQ ID NO:55]

DNA sequence [SEQ ID NO:54] codes for the foregoing polypeptide.

EXAMPLE 3 BHK Expression Vector for 1-153 c-mpl Ligand

The 1-153 c-mpl ligand gene product was digested with NcoI and HindIIIrestriction enzymes for subcloning into pMON3934. pMON3934, a mammalianexpression vector, is also derived from pMON3359, but it contains amodified human IL-3 signal peptide sequence in addition to the IE110promoter and poly-A signal. The signal peptide sequence is flanked byBamHI and NcoI restriction enzyme sites, which facilitates cloning andexpression of genes as NcoI-HindIII fragments. The HindIII site is 3' tothe NcoI site. The DNA sequence of the signal peptide is shown below(restriction enzyme sites are indicated above). The ATG (methionine)codon within the NcoI site is in-frame with the initiator ATG of thesignal peptide (underlined); BamHINcoIGGATCCACCATGAGCCGCCTGCCCGTCCTGCTCCTGCTCCAACTCCTGGTCCGCCCCGCCATGG[SEQ ID NO:58] MetSerArgLeuProValLeuLeuLeuLeuGlnLeuLeuValArgProAlaMet[SEQ ID NO:59]

The resulting plasmid was designated pMON26448. The plasmid, pMON26448,encodes the following amino acid sequence:

Met Glu Leu Thr Glu Leu Leu Leu Val Val Met Leu Leu Leu

Thr Ala Arg Leu Thr Leu Ser Ser Pro Ala Pro Pro Ala Cys

Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val

Leu His Ser Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu

Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly

Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln Asp Ile

Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala

Arg Gly Gln Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly

Gln Leu Ser Gly Gln Val Arg Leu Leu Leu Gly Ala Leu Gln

Ser Leu Leu Gly Thr Gln Leu Pro Pro Gln Gly Arg Thr Thr

Ala His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gln His

Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly

Ser Thr Leu Cys Val Arg [SEQ ID NO:56]

DNA sequence [SEQ ID NO:54] codes the foregoing amino acid sequence.

For secreted 1-153 c-mpl ligand, the N-terminal sequence should beSerProAla . . . , like that described elsewhere [de Sauvage et al.,(1994)]. For the 1-332 c-mpl ligand, which contains its own secretionsignal, it also should be cleaved to leave SerProAla . . . on theN-terminus. Therefore, the numbering system assumes that SerProAla . . .are the first three amino acids on either protein.

AML Proliferation Assay for Bioactive Human Interleukin-3

The factor-dependent cell line AML 193 was obtained from the AmericanType Culture Collection (ATCC, Rockville, Md.). This cell line,established from a patient with acute myelogenous leukemia, was a growthfactor dependent cell line which displayed enhanced growth in GM/CSFsupplemented medium (Lange, B., et al., (1987); Valtieri, M., et al.,(1987). The ability of AML 193 cells to proliferate in the presence ofhuman IL-3 has also been documented. (Santoli, D., et al., (1987)). Acell line variant was used, AML 193 1.3, which was adapted for long termgrowth in IL-3 by washing out the growth factors and starving thecytokine dependent AML 193 cells for growth factors for 24 hours. Thecells were then replated at 1×10⁵ cells/well in a 24 well plate in mediacontaining 100 U/ml IL-3. It took approximately 2 months for the cellsto grow rapidly in IL-3. These cells were maintained as AML 193 1.3thereafter by supplementing tissue culture medium (see below) with humanIL-3.

AML 193 1.3 cells were washed 6 times in cold Hanks balanced saltsolution (HBSS, Gibco, Grand Island, N.Y.) by centrifuging cellsuspensions at 250×g for 10 minutes followed by decantation ofsupernatant. Pelleted cells were resuspended in HBSS and the procedurewas repeated until six wash cycles were completed. Cells washed sixtimes by this procedure were resuspended in tissue culture medium at adensity ranging from 2×10⁵ to 5×10⁵ viable cells/ml. This medium wasprepared by supplementing Iscove's modified Dulbecco's Medium (IMDM,Hazelton, Lenexa, Kans.) with albumin, transferrin, lipids and2-mercaptoethanol. Bovine albumin (Boehringer-Mannheim, Indianapolis,Ind.) was added at 500 μg/ml; human transferrin (Boehringer-Mannheim,Indianapolis, Ind.) was added at 100 μg/ml; soybean lipid(Boehringer-Mannheim, Indianapolis, Ind.) was added at 50 μg/ml; and2-mercaptoethanol (Sigma, St. Louis, Mo.) was added at 5×10⁻⁵ M.

Serial dilutions of human interleukin-3 or human interleukin-3 variantprotein (hIL-3 mutein) were made in triplicate series in tissue culturemedium supplemented as stated above in 96 well Costar 3596 tissueculture plates. Each well contained 50 μl of medium containinginterleukin-3 or interleukin-3 variant protein once serial dilutionswere completed. Control wells contained tissue culture medium alone(negative control). AML 193 1.3 cell suspensions prepared as above wereadded to each well by pipetting 50 μl (2.5×10⁴ cells) into each well.Tissue culture plates were incubated at 37° C. with 5% CO₂ in humidifiedair for 3 days. On day 3, 0.5 μCi ³ H-thymidine (2 Ci/mM, New EnglandNuclear, Boston, Mass.) was added in 50 μl of tissue culture medium.Cultures were incubated at 37° C with 5% CO₂ in humidified air for 18-24hours. Cellular DNA was harvested onto glass filter mats (Pharmacia LKB,Gaithersburg, Md.) using a TOMTEC cell harvester (TOMTEC, Orange, Conn.)which utilized a water wash cycle followed by a 70% ethanol wash cycle.Filter mats were allowed to air dry and then placed into sample bags towhich scintillation fluid (Scintiverse II, Fisher Scientific, St. Louis,Mo. or BetaPlate Scintillation Fluid, Pharmacia LKB, Gaithersburg, Md.)was added. Beta emissions of samples from individual tissue culturewells were counted in a LKB Betaplate model 1205 scintillation counter(Pharmacia LKB, Gaithersburg, Md.) and data was expressed as counts perminute of ³ H-thymidine incorporated into cells from each tissue culturewell. Activity of each human interleukin-3 preparation or humaninterleukin-3 variant preparation was quantitated by measuring cellproliferation (³ H-thymidine incorporation) induced by gradedconcentrations of interleukin-3 or interleukin-3 variant. Typically,concentration ranges from 0.05 pM-10⁵ pM were quantitated in theseassays. Activity was determined by measuring the dose of interleukin-3or interleukin-3 variant which provides 50% of maximal proliferation[EC₅₀ =0.5×(maximum average counts per minute of ³ H-thymidineincorporated per well among triplicate cultures of all concentrations ofinterleukin-3 tested--background proliferation measured by ³ H-thymidineincorporation observed in triplicate cultures lacking interleukin-3].This EC₅₀ value is also equivalent to 1 unit of bioactivity. Every assaywas performed with native interleukin-3 as a reference standard so thatrelative activity levels could be assigned.

Methylcellulose Assay

This assay provides a reasonable approximation of the growth activity ofcolony stimulating factors to stimulate normal bone marrow cells toproduce different types of hematopoietic colonies in vitro (Bradley etal., 1966, Pluznik et al., 1965).

Methods

Approximately 30 ml of fresh, normal, healthy bone marrow aspirate areobtained from individuals. Under sterile conditions samples are diluted1:5 with a 1×PBS (#14040.059 Life Technologies, Gaithersburg, Md.)solution in a 50 ml conical tube (#25339-50 Corning, Corning Md.).Ficoll (Histopaque-1077 Sigma H-8889) is layered under the dilutedsample and centrifuged, 300×g for 30 min. The mononuclear cell band isremoved and washed two times in 1×PBS and once with 1% BSA PBS (CellProCo., Bothel, Wash.). Mononuclear cells are counted and CD34+ cells areselected using the Ceprate LC (CD34) Kit (CellPro Co., Bothel, Wash.)column. This fractionation is performed since all stem and progenitorcells within the bone marrow display CD34 surface antigen. Alternativelywhole bone marrow or peripheral blood may be used.

Cultures are set up in triplicate wells with a final volume of 0.1 ml in48 well tissue culture plates (#3548 CoStar, Cambridge, Mass.). Culturemedium is purchased from Terry Fox Labs. (HCC-4330 medium (Terry FoxLabs, Vancouver, B.C., Canada)). 600-1000 CD34+ cells are added perwell. Native IL-3 and IL-3 variants are added to give finalconcentrations ranging from 0.001 nM-10 nM. G-CSF and GM-CSF and C-Kitligand are added at a final concentration of 0.1 nM. Native IL-3 andIL-3 variants are supplied in house. C-Kit Ligand (#255-CS), G-CSF(#214-CS) and GM-CSF (#215-GM) are purchased from R&D Systems(Minneapolis, Minn.). Cultures are resuspended using an Eppendorfrepeater and 0.1 ml is dispensed per well. Control (baseline response)cultures received no colony stimulating factors. Positive controlcultures received conditioned media (PHA stimulated human cells:TerryFox Lab. H2400). Cultures are incubated at 37° C., 5% CO₂ in humidifiedair.

Hematopoietic colonies which are defined as greater than 50 cells arecounted on the day of peak response (days 10-11) using a Nikon invertedphase microscope with a 40× objective combination. Groups of cellscontaining fewer than 50 cells are referred to as clusters.Alternatively colonies can be identified by spreading the colonies on aslide and stained or they can be picked, resuspended and spun ontocytospin slides for staining.

EXAMPLE 4

The synergistic effect of the IL-3 variant, pMON13288, with G-CSF wasevaluated in the methylcellulose assay compared to that of native IL-3with G-CSF. G-CSF was added to each culture at a concentration of 0.1nM. Native IL-3 and the IL-3 variant, pMON13288, were added at finalconcentrations ranging from 0.001 nM to 10 nM. Colonies were counted onthe day of peak response (days 10-11). pMON13288 activates moreprogenitor cells than native IL-3 (FIG. 2). Native IL-3 plus G-CSF andthe IL-3 variant, pMON13288, plus G-CSF resulted in an increase incolony number greater than the additive effect of the individualproteins alone (FIG. 2). The synergistic effect of the IL-3 variant,pMON13288, with G-CSF was greater than that of native IL-3 with G-CSF.Hematopoietic colony forming activity of the IL-3 variant, pMON13288,was multi-lineage whereas G-CSF alone activates primarily granulocyticcells at molar equivalent doses. In FIG. 2 the concentration of IL-3 isplotted versus the colony counts per 100,000 starting CD34+ cells.

EXAMPLE 5

The synergistic effect of the IL-3 variant, pMON13288, with GM-CSF wasevaluated in the methylcellulose assay compared to that of native IL-3with GM-CSF. GM-CSF was added to each culture at a concentration of 0.1nM. Native IL-3 and the IL-3 variant, pMON13288, were added at finalconcentrations ranging from 0.001 nM to 10 nM. Colonies were counted onthe day of peak response (days 10-11). pMON13288 activates moreprogenitor cells than native IL-3 (FIG. 3). Native IL-3 plus GM-CSF andthe IL-3 variant, pMON13288, plus GM-CSF resulted in an increase incolony number greater than the effect of the individual proteins alone(FIG. 3). The synergistic effect of the IL-3 variant, pMON13288, withGM-CSF was greater than that of native IL-3 with GM-CSF. In FIG. 3 theconcentration of IL-3 is plotted versus the colony counts per 100,000starting CD34+ cells.

EXAMPLE 6

Methylcellulose assays for native IL-3, pMON5873, were carried out inmethylcellulose, with or without EPO. Although EPO increased the totalnumber of colonies, it didn't appear to increase CFU-GM, which are ofmore interest. The presence of erythroid colonies also made scoring moresubjective, because one must distinguish between multifocal BFU-E vsseveral closely associated single focus CFU-E. EPO also gave a highbackground of total colonies, which would tend to obscure the dosedependent response of CFU-GM to other CSFs.

Methylcellulose assays comparing native IL-3 (pMON5873) to the IL-3variant, pMON13288 were carried out in the presence of stem cell factor(SCF) without EPO. SCF gives no background response in these assays, butappears to increase the dose dependent response of CFU-GM to both nativeIL-3 (PMON5873) and the IL-3 variant, pMON13288. This result isconsistent with reports in the literature of in vitro synergies betweenIL-3 and SCF (Migliaccio et al., 1992). The IL-3 variant, pMON13288,appears to be more potent in these assays, and gives a greater maximumnumber of colonies (also larger) than native IL-3 (PMON5873).

Human Cord Blood Hemopoietic Growth Factor Assays

Bone marrow cells are traditionally used for in vitro assays ofhematopoietic colony stimulating factor (CSF) activity. However, humanbone marrow is not always available, and there is considerablevariability between donors. Umbilical cord blood is comparable to bonemarrow as a source of hematopoietic stem cells and progenitors(Broxmeyer et al., 1992; Mayani et al., 1993). In contrast to bonemarrow, cord blood is more readily available on a regular basis. Thereis also a potential to reduce assay variability by pooling cellsobtained fresh from several donors, or to create a bank of cryopreservedcells for this purpose. By modifying the culture conditions, and/oranalyzing for lineage specific markers, it should be possible to assayspecifically for granulocyte/macrophage colonies (CFU-GM), formegakaryocyte CSF activity, or for high proliferative potential colonyforming cell (HPP-CFC) activity.

METHODS

Mononuclear cells (MNC) are isolated from cord blood within 24 hrs ofcollection, using a standard density gradient (1.077 g/ml Histopaque).Cord blood MNC have been further enriched for stem cells and progenitorsby several procedures, including immunomagnetic selection for CD14-,CD34+ cells; panning for SBA-, CD34+fraction using coated flasks fromApplied Immune Science (Santa Clara, Calif.); and CD34+ selection usinga CellPro (Bothell, Wash.) avidin column. Either freshly isolated orcryopreserved CD34+ cell enriched fractions are used for the assay.Duplicate cultures for each serial dilution of sample (concentrationrange from 1 pM to 1204 pM) are prepared with 1×104 cells in 1 ml of0.9% methycellulose containing medium without additional growth factors(Methocult H4230 from Stem Cell Technologies, Vancouver, BC.). In someexperiments, Methocult H₄₃₃₀ containing erythropoietin (EPO) was usedinstead of Methocult H4230, or Stem Cell Factor (SCF), 50 ng/ml(Biosource International, Camarillo, Calif.) was added. After culturingfor 7-9 days, colonies containing >30 cells are counted. In order torule out subjective bias in scoring, assays are scored blind.

Analysis of c-mpl Ligand Proliferative Activity

METHODS

1. Bone Marrow Proliferation Assay

a. CD34+ Cell Purification:

Between 15-20 ml bone marrow aspirates were obtained from normalallogeneic marrow donors after informed consent. Cells were diluted 1:3in phosphate buffered saline (PBS, Gibco-BRL), 30 ml were layered over15 ml Histopaque-1077 (Sigma) and centrifuged for 30 minutes at 300 RCF.The mononuclear interface layer was collected and washed in PBS. CD34+cells were enriched from the mononuclear cell preparation using anaffinity column per manufacturers instructions (CellPro, Inc, BothellWash.). After enrichment, the purity of CD34+ cells was 70% on averageas determined by using flow cytometric analysis using anti CD34monoclonal antibody conjugated to fluorescein and anti CD38 conjugatedto phycoerythrin (Becton Dickinson, San Jose Calif.).

Cells were resuspended at 40,000 cells/ml in X-Vivo 10 media(Bio-Whittaker, Walkersville, Md.) and 1 ml was plated in 12-well tissueculture plates (Costar). The growth factor rhIL-3 was added at 100 ng/ml(pMON5873) was added to some wells. hIL3 variant, pMON13288 was used at10 ng/ml or 100 ng/ml. Conditioned media from BHK cells transfected withplasmid encoding c-mpl ligand were tested by addition of 100 μl ofsupernatant added to 1 ml cultures (approximately a 10% dilution). Cellswere incubated at 37° C. for 8-14 days at 5% CO₂ in a 37° C. humidifiedincubator.

b. Cell Harvest and Analysis:

At the end of the culture period a total cell count was obtained foreach condition. For fluorescence analysis and ploidy determination cellswere washed in megakaryocyte buffer (MK buffer, 13.6 mM Sodium Citrate,1 mM Theophylline, 2.2 μM PGE1, 11 mM Glucose, 3% w/v BSA, in PBS, pH7.4,) [See Tomer et al., Blood 70, 1987, pp. 1736-42] resuspended in 500μl of MK buffer containing anti-CD41a FITC antibody (1:200, AMAC,Westbrook, Me.) and washed in MK buffer. For DNA analysis cells werepermeablized in MK buffer containing 0.5% Tween 20 (Fisher, Fair LawnN.J.) for 20 min. on ice followed by fixation in 0.5% Tween-20 and 1%paraformaldehyde (Fisher Chemical) for 30 minutes followed by incubationin Propidium Iodide (Calbiochem , La Jolla Calif.) (50 μg/ml) withRNA-ase (400 U/ml) in 55% v/v MK buffer (200 mOsm) for 1-2 hours on ice.Cells were analyzed on a FACScan or Vantage flow cytometer (BectonDickinson, San Jose, Calif.). Green fluorescence (CD41a-FITC) wascollected along with linear and log signals for red fluorescence (PI) todetermine DNA ploidy. All cells were collected to determine the percentof cells that were CD41+. Data analysis was performed using software byLYSIS (Becton Dickinson, San Jose, Calif.). Percent of cells expressingthe CD41 antigen was obtained from flow cytometry analysis(Percent).Absolute (Abs) number of CD41+ cells/ml was calculated by: (Abs)=(CellCount)*(Percent)/100.

2. Megakaryocyte Fibrin Clot Assay.

CD34+ enriched population were isolated as described above. Cells weresuspended at 25,000 cells/ml with/without cytokine(s) in a mediaconsisting of a base Iscoves IMDM media supplemented with 0.3% BSA, 0.4mg/ml apo-transferrin, 6.67 μM FeCl₂, 25 μg/ml CaCl₂, 25 μg/mlL-asparagine, 500 μg/ml E-amino-n-caproic acid andPenicillin/Streptomycin. Prior to plating into 35 mm plates, thrombinwas added (0.25 Units/ml) to initiate clot formation. Cells wereincubated at 37° C. for 13 days at 5% CO₂ in a 37° C. humidifiedincubator. At the end of the culture period plates were fixed withMethanol:Acetone (1:3), air dried and stored at -20° C. until staining.A peroxidase immunocytochemistry staining procedure was used (Zymed,Histostain-SP. San Francisco, Calif.) using a cocktail of primarymonoclonal antibodies consisting of anti CD41a, CD42 and CD61. Colonieswere counted after staining and classified as negative, CFU-MK (smallcolonies, 1-2 foci and less that approx. 25 cells), BFU-MK (large,multi-foci colonies with >25 cells) or mixed colonies (mixture of bothpositive and negative cells).

EXAMPLE 7 Co-administration of hIL-3 Variant, pMON13288 and c-mpl Ligand(Meg-CSF) in Liquid Culture

Co-administration of hIL-3 variant, pMON13288 and c-mpl ligand (Meg-CSF)has a more than additive effect on megakaryocyte expansion than eithercytokine alone in the liquid culture assay

CD34+ cells were isolated as described in the methods section. The assaywas set up as described in the methods section except that cells wereplated at 4000 cells/100 μl in a 96-well plate. pMON26448 or a mocktransfectant was evaluated by adding 10 μl to each well (10% final).Supernatant from transfected BHK cells were tested +/- hIL3 variant,pMON13288 (10 ng/ml). At day 10 phenotypic analysis was performed byflow cytometry. Supernatant from pMON26448 induced selective expansionof CD41a+ cells. Total cell number increased from the 4000 cells platedto 22,000 at the end of the assay (Table 1). Addition of hIL3 variant,pMON13288 alone increased total cell numbers (19,000 cells at end ofassay) with 17% of cells expressing CD41a. Combination of pMON26448 withhIL3 variant, pMON13288 resulted in 56% of cells expressing CD41a. Totalcell expansion in the combination assay was more than additive with86,000 cells/well. Both the increased total cell number and the higherpercentage of cells expressing CD41a resulted in an increase in totalnumber CD41+ cells that also was more than additive as compared toeither cytokine alone (48,000 vs. 3,320 and 18,480).

                  TABLE 1                                                         ______________________________________                                        Cytokine               % CD41a  # CD41 +                                      Treatment  Cells/Well  Positive Cells/Well                                    ______________________________________                                        pMON13288  19,000      17        3,230                                        pMON26448  22,000      84       18,480                                        pMON26448 +                                                                              86,000      56       48,160                                        pMON13288                                                                     ______________________________________                                    

EXAMPLE 8 Co-administration of hIL-3 Variant, pMON13288, and c-mplLigand (Meg-CSF) in Liquid Culture

The co-administration of hIL-3 variant, pMON13288, and c-mpl ligand(Meg-CSF) has a more than additive effect on megakaryocyte expansionthan either cytokine alone in the liquid culture assay

In another experiment CD34+ cells were isolated from Human bone marrowusing a CD34 affinity column (Cellpro). Purified CD34+ cells wereresuspended in X-vivo tissue culture media at 40,000 cells/ml. pMON26448or a mock transfectant (10%) was evaluated with/without hIL3 variant,pMON13288 or native IL3. At day 8 phenotypic analysis was done usingflow cytometry. As was seen in the table below (Table 2a-c). IL3, bothconcentrations of hIL3 variant, pMON13288 and pMON26448 increased totalcell number substantially. Combination of cytokines further expandedcell populations. pMON26448 increased the percent of CD41+ cells from 2%in the control group to 35%. IL3 or hIL3 variant, pMON13288 increasedthe percent of CD41+ cells modestly (from 2% to 5%). Combining pMON26448with IL3 or hIL3 variant, pMON13288 resulted in a more than additivenumber of CD41+ cells as compared to the sum of either cytokine alone(Table 2c).

                  TABLE 2(a-c)                                                    ______________________________________                                        a. Total Cells/Well                                                           Cytokine          IL-3      pMON13288                                                                              pMON13288                                treatment                                                                             Media     (100 ng/ml)                                                                             (10 ng/ml)                                                                             (100 ng/ml)                              ______________________________________                                        Media   30,000    112,000   275,000  150,000                                  Mock    10,000    153,000   235,000  260,000                                  pMON26448                                                                             135,000   655,000   625,000  500,000                                  ______________________________________                                        b. % CD41a +                                                                  Media   2          7        5        5                                        Mock    2         14        5        9                                        pMON26448                                                                             35        35        28       29                                       ______________________________________                                        c. Total CD41a + Cells                                                        Media   600        7,840    13,750    7,500                                   Mock    200       21,420    11,750   23,400                                   pMON26448                                                                             47,250    229,250   175,000  145,000                                  ______________________________________                                    

EXAMPLE 9 Co-administration of hIL-3 Variant, pMON13288, and c-mplLigand (Meg-CSF) in Fibrin Clot Assay

The co-administration of hIL-3 variant, pMON13288, and c-mpl ligand(Meg-CSF) has a more than additive effect on megakaryocyte than eithercytokine alone.

Fibrin clot cultures were set up as described in methods section.pMON26448 is the 1-153 form of c-mpl ligand (Meg-CSF). Incubation in thepresence of hIL3 variant, pMON13288 gave rise to colonies that werepredominantly negative for megakaryocyte markers (86/114, (Table 3))except for number of small CFU-MK colonies (23/114). pMON26448 alonegave rise primarily to CFU-MK colonies (172/175) with only a few numberof negative colonies (3/175). Combination of hIL3 variant, pMON13288 andpMON26448 gave rise to a large number of positive colonies (295/414)that were predominantly of the BFU-MK morphology. There were a negativecolonies as well (119/414). Total number of positive colonies withco-administration was more than additive than with either cytokinealone.

                  TABLE 3                                                         ______________________________________                                        Cytokine                                Total                                 treatment                                                                              Negative CFU-MK   BFU-MK Mixed Colonies                              ______________________________________                                        Colonies/Well                                                                 pMON13288                                                                               86      23        0      5    114                                   pMON26448                                                                               3       73        98     1    175                                   pMON26448 +                                                                            119      29       244    22    414                                   pMON13288                                                                     Colonies/100,000 plated                                                       pMON13288                                                                              344      92        0     20    456                                   pMON26448                                                                               12      292      392     4    700                                   pMON26448 +                                                                            476      116      976    88    1656                                  pMON13288                                                                     ______________________________________                                    

IL-3 Mediated Sulfidoleukotriene Release from Human Mononuclear Cells

The following assay was used to measure IL-3 mediated sulfidoleukotrienerelease from human mononuclear cells.

Heparin-containing human blood was collected and layered onto an equalvolume of Ficoll-Paque (Pharmacia # 17-0840-02) ready to use medium(density 1.077 g/ml.). The Ficoll was warmed to room temperature priorto use and clear 50 ml polystyrene tubes were utilized. The Ficollgradient was spun at 300×g for 30 minutes at room temperature using aH1000B rotor in a Sorvall RT6000B refrigerated centrifuge. The bandcontaining the mononuclear cells was carefully removed, the volumeadjusted to 50 mls with Dulbecco's phosphate-buffered saline (GibcoLaboratories cat. # 310-4040PK), spun at 400×g for 10 minutes at 4° C.and the supernatant was carefully removed. The cell pellet was washedtwice with HA Buffer [20 mM Hepes (Sigma # H-3375), 125 mM NaCl (Fisher# S271-500), 5 mM KCl (Sigma # P-9541), 0.5 mM glucose (Sigma # G-5000),0.025% Human Serum Albumin (Calbiochem # 126654) and spun at 300×g, 10min., 4° C. The cells were resuspended in HACM Buffer (HA buffersupplemented with 1 mM CaCl₂ (Fisher # C79-500) and 1 mM MgCl2 (Fisher #M-33) at a concentration of 1×106 cells/ml and 180 μl were transferredinto each well of 96 well tissue culture plates. The cells were allowedto acclimate at 37° C. for 15 minutes. The cells were primed by adding10 μls of a 20×stock of various concentrations of cytokine to each well(typically 100000, 20000, 4000, 800, 160, 32, 6.4, 1.28, 0 fM IL3). Thecells were incubated for 15 minutes at 37° C. Sulfidoleukotriene releasewas activated by the addition of 10 μls of 20×(1000 nM) fmet-leu-phe(Calbiochem # 344252) final concentration 50 nM FMLP and incubated for10 minutes at 37° C. The plates were spun at 350×g at 4° C. for 20minutes. The supernatants were removed and assayed forsulfidoleukotrienes using Cayman's Leukotriene C4 EIA kit (Cat. #420211)according to manufacturers' directions. Native (15-125)hIL-3 was run asa standard control in each assay.

Further details known to those skilled in the art may be found in T.Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold SpringHarbor Laboratory (1982) and references cited therein, incorporatedherein by reference; and in J. Sambrook, et al., Molecular Cloning, ALaboratory Manual, 2nd edition, Cold Spring Harbor Laboratory (1989) andreferences cited therein, incorporated herein by reference.

Amino acids are shown herein by standard one letter or three letterabbreviations as follows:

    ______________________________________                                        Abbreviated Designation    Amino Acid                                         ______________________________________                                        A         Ala              Alanine                                            C         Cys              Cysteine                                           D         Asp              Aspartic acid                                      E         Glu              Glutamic acid                                      F         Phe              Phenylalanine                                      G         Gly              Glycine                                            H         His              Histidine                                          I         Ile              Isoleucine                                         K         Lys              Lysine                                             L         Leu              Leucine                                            M         Met              Methionine                                         N         Asn              Asparagine                                         P         Pro              Proline                                            Q         Gln              Glutamine                                          R         Arg              Arginine                                           S         Ser              Serine                                             T         Thr              Threonine                                          V         Val              Valine                                             W         Trp              Tryptophan                                         Y         Tyr              Tyrosine                                           ______________________________________                                    

Additional details may be found in co-pending U.S. patent applicationSer. No. PCT/US93/11197 which is hereby incorporated by reference in itsentirety as if written herein.

All references, patents or applications cited herein are incorporated byreference in their entirety as if written herein.

Various other examples will be apparent to the person skilled in the artafter reading the present disclosure without departing from the spiritand scope of the invention. It is intended that all such other examplesbe included within the scope of the appended claims.

                  TABLE 4                                                         ______________________________________                                        OLIGONUCLEOTIDES                                                              ______________________________________                                        c-mplBglII                                                                    CATGGCAAGATCTCCGGCCAGAATGGAGCTGACTGA [SEQ ID NO:50]                           c-mplEcoRI                                                                    AATAGCTGAATTCTTACCCTTCCTGAGACAGATT [SEQ ID NO:51]                             c-mplNcoI                                                                     ACGTCCATGGCNTCNCCNGCNCCNCCTGCTTGTGACCTCCGAGTC                                 [SEQ ID NO:52]                                                                (where N = G, C, T or A)                                                      c-mplHindIII                                                                  TGACAAGCTTACCTGACGCAGAGGGTGGACCCT [SEQ ID NO:53]                              ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    DNA SEQUENCES                                                                 __________________________________________________________________________    1-153 c-mpl ligand                                                            ATGGCGTCTC CGGCGCCGCC TGCTTGTGAC CTCCGAGTCC TCAGTAAACT                                                         [SEQ ID NO:54]                               GCTTCGTGAC TCCCATGTCC TTCACAGCAG ACTGAGCCAG TGCCCAGAGG                        TTCACCCTTT GCCTACACCT GTCCTGCTGC CTGCTGTGGA CTTTAGCTTG                        GGAGAATGGA AAACCCAGAT GGAGGAGACC AAGGCACAGG ACATTCTGGG                        AGCAGTGACC CTTCTGCTGG AGGGAGTGAT GGCAGCACGG GGACAACTGG                        GACCCACTTG CCTCTCATCC CTCCTGGGGC AGCTTTCTGG ACAGGTCCGT                        CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAACCCAGC TTCCTCCACA                        GGGCAGGACC ACAGCTCACA AGGATCCCAA TGCCATCTTC CTGAGCTTCC                        AACACCTGCT CCGAGGAAAG GTGCGTTTCC TGATGCTTGT AGGAGGGTCC                        ACCCTCTGCG TCAGG                                                              Full length c-mpl ligand                                                      ATGGAGCTGA CTGAATTGCT CCTCGTGGTC ATGCTTCTCC TAACTGCAAG                                                         [SEQ ID NO:57]                               GCTAACGCTG TCCAGCCCGG CTCCTCCTGC TTGTGACCTC CGAGTCCTCA                        GTAAACTGCT TCGTGACTCC CATGTCCTTC ACAGCAGACT GAGCCAGTGC                        CCAGAGGTTC ACCCTTTGCC TACACCTGTC CTGCTGCCTG CTGTGGACTT                        TAGCTTGGGA GAATGGAAAA CCCAGATGGA GGAGACCAAG GCACAGGACA                        TTCTGGGAGC AGTGACCCTT CTGCTGGAGG GAGTGATGGC AGCACGGGGA                        CAACTGGGAC CCACTTGCCT CTCATCCCTC CTGGGGCAGC TTTCTGGACA                        GGTCCGTCTC CTCCTTGGGG CCCTGCAGAG CCTCCTTGGA ACCCAGCTTC                        CTCCACAGGG CAGGACCACA GCTCACAAGG ATCCCAATGC CATCTTCCTG                        AGCTTCCAAC ACCTGCTCCG AGGAAAGGTG CGTTTCCTGA TGCTTGTAGG                        AGGGTCCACC CTCTGCGTCA GGCGGGCCCC ACCCACCACA GCTGTCCCCA                        GCAGAACCTC TCTAGTCCTC ACACTGAACG AGCTCCCAAA CAGGACTTCT                        GGATTGTTGG AGACAAACTT CACTGCCTCA GCCAGAACTA CTGGCTCTGG                        GCTTCTGAAG TGGCAGCAGG GATTCAGAGC CAAGATTCCT GGTCTGCTGA                        ACCAAACCTC CAGGTCCCTG GACCAAATCC CCGGATACCT GAACAGGATA                        CACGAACTCT TGAATGGAAC TCGTGGACTC TTTCCTGGAC CCTCACGCAG                        GACCCTAGGA GCCCCGGACA TTTCCTCAGG AACATCAGAC ACAGGCTCCC                        TGCCACCCAA CCTCCAGCCT GGATATTCTC CTTCCCCAAC CCATCCTCCT                        ACTGGACAGT ATACGCTCTT CCCTCTTCCA CCCACCTTGC CCACCCCTGT                        GGTCCAGCTC CACCCCCTGC TTCCTGACCC TTCTGCTCCA ACGCCCACCC                        CTACCAGCCC TCTTCTAAAC ACATCCTACA CCCACTCCCA GAATCTGTCT                        CAGGAAGGGG                                                                    __________________________________________________________________________

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Taylor, J. W., Ott, J. and Eckstein, F. The rapid generation ofoligonucleotide-directed mutants at high frequency usingphosphorothioate modified DNA. Nucl. Acids Res., 13:8764-8785 (1985).

Tomer, A., Harker, L. A., and Burstein, S. A. Purification of humanmegakaryocytes by Fluoresence-activated cell sorting. Blood70(6):1735-1742 (1987).

Treco, D. A., (1989) in Current protocols in Molecular Biology, Seidmanet al., eds. J Wiley N.Y., unit 2.1.

Valtieri, M., D. Santoli, D. Caracciolo, B. L. Kreider, S. W. Altmann,D. J. Tweardy, I. Gemperlein, F. Mavilio, B. J. Lange and G. Rovera.Establishment and characterization of an undifferentiated human Tleukemia cell line which requires granulocyte-macrophage colonystimulating factor for growth. J. Immunol. 138:4042 (1987).

Voet, D., W. B. Gatzer, R. A. Cox, P. Doty. Absorption spectra of thecommon bases. Biopolymers 1: 193 (1963).

Weinberg, R. A., De Ciechi, P. A., Obukowicz, M.: A chromosomalexpression vector for Escherichia coli based on the bacteriophage Mu.Gene 126 (1993) 25-33.

Wells, J. A., Vasser, M., and Powers, D. B. Cassette mutagenesis: aneffective method for generation of multiple mutants at defined sites.Gene, 34:315-323 (1985).

Wong, Y. Y., R. Seetharam, C. Kotts, R. A. Heeren, B. K. Klein, S. B.Braford, K. J. Mathis, B. F. Bishop, N. R. Siegel, C. E. Smith and W. C.Tacon. Expression of secreted IGF-1 in Escherichia coli. Gene, 68:193-203 (1988).

Yanisch-Perron, C., J. Viera and J. Messing. Improved M13 phage cloningvectors and host strains: nucleotide sequences of the M13mpl8 and pUC19vectors. Gene 33: 103-119 (1985).

Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B.,Taniguchi, T., Hirano, T., Kishimoto, T.: Cloning and expression of thehuman interleukin-6 (BSF-2?IFN beta 2) receptor. Science 241:825, 1988

Yarden Y., Kuang, W-J., Yang-Feng, T., Coussens, L., Munemitsu, S.,Dull, T. J., Chen, E., Schlesinger, J., Francke, U., Ullrich, A., Humanproto-oncogene c-kit: A new cell surface receptor tyrosine kinase for anunidentified ligand. EMBO J 6:3341, 1987

Zoller, M. J. and Smith, M. oligonucleotide-directed mutagenesis usingM13-derived vectors: an efficient and general procedure for theproduction of point mutations in any fragment of DNA. Nucleic AcidResearch, 10: 6487-6500 (1982).

Zoller, M. J. and Smith, M. Oligonucleotide-directed mutagenesis of DNAfragments cloned into M13 vectors. Methods in Enzymology, 100:468-500(1983).

Zoller, M. J. and Smith, M. Oligonucleotide-directed Mutagenesis: Asimple method using two oligonucleotide primers and a single-strandedDNA template. DNA, 3: 479 (1984).

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 58                                            - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 133 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- may or may not precede                                                         the amino - # acid in position 1"                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 17                                                    #/note= "Xaa at position 17 is Ser,                                                          Lys, Gly, - # Asp, Met, Gln, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Asn,                                                          His, Leu, - # Ile, Phe, Arg, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 19                                                    #/note= "Xaa at positiion 19 is Met,                                                         Phe, Ile, - # Arg, Gly, Ala, or Cys"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Ile,                                                          Cys, Gln, - # Glu, Arg, Pro, or Ala"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 21                                                    #/note= "Xaa at position 21 is Asp,                                                          Phe, Lys, - # Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser,                         or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 22                                                    #/note= "Xaa at position 22 is Glu,                                                          Trp, Pro, - # Ser, Ala, His, Asp, Asn, Gln, Leu, Val,                         or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Ile,                                                          Val, Ala, - # Leu, Gly, Trp, Lys, Phe, Ser, or                                Arg"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Ile,                                                          Gly, Val, - # Arg, Ser, Phe, or Leu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 25                                                    #/note= "Xaa at position 25 is Thr,                                                          His, Gly, - # Gln, Arg, Pro, or Ala"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 26                                                    #/note= "Xaa at position 26 is His,                                                          Thr, Phe, - # Gly, Arg, Ala, or Trp"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 27                                                    #/note= "Xaa at position 27 is Leu,                                                          Gly, Arg, - # Thr, Ser, or Ala"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 28                                                    #/note= "Xaa at position 28 is Lys,                                                          Arg, Leu, - # Gln, Gly, Pro, Val, or Trp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 29                                                    #/note= "Xaa at position 29 is Gln,                                                          Asn, Leu, - # Pro, Arg, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 30                                                    #/note= "Xaa at position 30 is Pro,                                                          His, Thr, - # Gly, Asp, Gln, Ser, Leu, or Lys"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Pro,                                                          Asp, Gly, - # Ala, Arg, Leu, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Leu,                                                          Val, Arg, - # Gln, Asn, Gly, Ala, or Glu"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 33                                                    #/note= "Xaa at position 33 is Pro,                                                          Leu, Gln, - # Ala, Thr, or Glu"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 34                                                    #/note= "Xaa at position 34 is Leu,                                                          Val, Gly, - # Ser, Lys, Glu, Gln, Thr, Arg, Ala, Phe,          #Met"          Ile, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 35                                                    #/note= "Xaa at position 35 is Leu,                                                          Ala, Gly, - # Asn, Pro, Gln, or Val"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 36                                                    #/note= "Xaa at position 36 is Asp,                                           #Val"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Phe,                                                          Ser, Pro, - # Trp, or Ile"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 38                                                    #/note= "Xaa at position 38 is Asn,                                                          or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 40                                                    #/note= "Xaa at position 40 is Leu,                                           #Arg"          Trp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 41                                                    #/note= "Xaa at position 41 is Asn,                                                          Cys, Arg, - # Leu, His, Met, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Gly,                                                          Asp, Ser, - # Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr      - #,                                                                                         Ile, Met, - # or Ala"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 43                                                    #/note= "Xaa at position 43 is Glu,                                                          Asn, Tyr, - # Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr, Gly      - #,                                                                                         or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 44                                                    #/note= "Xaa at position 44 is Asp,                                                          Ser, Leu, - # Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln, Ala      - #,                                                                                         or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Gln,                                                          Pro, Phe, - # Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg      - #,                                                                                         Ser, Ala, - # Ile, Glu, or His"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Asp,                                                          Phe, Ser, - # Thr, Cys, Glu, Asn, Gln, Lys, His, Ala, Tyr      - #,                                                                                         Ile, Val, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 47                                                    #/note= "Xaa at position 47 is Ile,                                                          Gly, Val, - # Ser, Arg, Pro, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 48                                                    #/note= "Xaa at position 48 is Leu,                                                          Ser, Cys, - # Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met      - #,                                                                          #Asn"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 49                                                    #/note= "Xaa at position 49 is Met,                                                          Arg, Ala, - # Gly, Pro, Asn, His, or Asp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Glu,                                                          Leu, Thr, - # Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His      - #,                                                                                         Phe, Met, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Asn,                                                          Arg, Met, - # Pro, Ser, Thr, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 52                                                    #/note= "Xaa at position 52 is Asn,                                                          His, Arg, - # Leu, Gly, Ser, or Thr"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 53                                                    #/note= "Xaa at position 53 isN:                                                             Leu, Thr, - # Ala, Gly, Glu, Pro, Lys, Ser, or Met"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 54                                                    #/note= "Xaa at position 54 is Arg,                                                          Asp, Ile, - # Ser, Val, Thr, Gln, Asn, Lys, His, Ala,                         or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Arg,                                                          Thr, Val, - # Ser, Leu, or Gly"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 56                                                    #/note= "Xaa at position 56 is Pro,                                                          Gly, Cys, - # Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr,                         Phe, Leu, - # Val, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 57                                                    #/note= "Xaa at position 57 is Asn                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 58                                                    #/note= "Xaa at position 58 is Leu,                                                          Ser, Asp, - # Arg, Gln, Val, or Cys"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 59                                                    #/note= "Xaa at position 59 is Glu,                                                          Tyr, His, - # Leu, Pro, or Arg"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 60                                                    #/note= "Xaa at position 60 is Ala,                                                          Ser, Pro, - # Tyr, Asn, or Thr"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 61                                                    #/note= "Xaa at position 61 is Phe,                                                          Asn, Glu, - # Pro, Lys, Arg, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Asn,                                                          His, Val, - # Arg, Pro, Thr, Asp, or Ile"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Arg,                                                          Tyr, Trp, - # Lys, Ser, His, Pro, or Val"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 64                                                    #/note= "Xaa at position 64 is Ala,                                                          Asn, Pro, - # Ser, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Val,                                                          Thr, Pro, - # His, Leu, Phe, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 66                                                    #/note= "Xaa at position 66 is Lys,                                                          Ile, Arg, - # Val, Asn, Glu, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Ser,                                                          Ala, Phe, - # Val, Gly, Asn, Ile, Pro, or His"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Val, Trp, - # Ser, Ile, Phe, Thr, or His"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Gln,                                                          Ala, Pro, - # Thr, Glu, Arg, Trp, Gly, or Leu"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 70                                                    #/note= "Xaa at position 70 is Asn,                                                          Leu, Val, - # Trp, Pro, or Ala"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 71                                                    #/note= "Xaa at position 71 isN:                                                             Ala, Met, - # Leu, Pro, Arg, Glu, Thr, Gln, Trp,                              or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 72                                                    #/note= "Xaa at position 72 is Ser,                                                          Glu, Met, - # Ala, His, Asn, Arg, or Asp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Ala,                                                          Glu, Asp, - # Leu, Ser, Gly, Thr, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 74                                                    #/note= "Xaa at position 74 is Ile,                                                          Met, Thr, - # Pro, Arg, Gly, or Ala"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 75                                                    #/note= "Xaa at position 75 isN:                                                             Glu, Lys, - # Gly, Asp, Pro, Trp, Arg, Ser, Gln,                              or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 76                                                    #/note= "Xaa at position 76 is Ser,                                                          Val, Ala, - # Asn, Trp, Glu, Pro, Gly, or Asp"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ile,                                                          Ser, Arg, - # Thr, or Leu"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 78                                                    #/note= "Xaa at position 78 is Leu,                                                          Ala, Ser, - # Glu, Phe, Gly, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Lys, Thr,                                                     Asn, Met, - # Arg, Ile, Gly, or Asp"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 80                                                    #/note= "Xaa at position 80 is Asn,                                                          Trp, Val, - # Gly, Thr, Leu, Glu, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 81                                                    #/note= "Xaa at position 81 is Leu,                                                          Gln, Gly, - # Ala, Trp, Arg, Val, or Lys"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Leu,                                                          Gln, Lys, - # Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala      - #,                                                                                         Tyr, Phe, - # Ile, Met, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 83                                                    #/note= "Xaa at position 83 is Pro,                                                          Ala, Thr, - # Trp, Arg, or Met"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 84                                                    #/note= "Xaa at position 84 is Cys,                                                          Glu, Gly, - # Arg, Met, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 is Leu,                                                          Asn, Val, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 86                                                    #/note= "Xaa at position 86 is Pro,                                                          Cys, Arg, - # Ala, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Leu,                                                          Ser, Trp, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 88                                                    #/note= "Xaa at position 88 is Ala,                                                          Lys, Arg, - # Val, or Trp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 89                                                    #/note= "Xaa at position 89 is Thr,                                                          Asp, Cys, - # Leu, Val, Glu, His, Asn, or Ser"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 90                                                    #/note= "Xaa at position 90 is Ala,                                                          Pro, Ser, - # Thr, Gly, Asp, Ile, or Met"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Ala,                                                          Pro, Ser, - # Thr, Phe, Leu, Asp, or His"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 92                                                    #/note= "Xaa at position 92 is Pro,                                                          Phe, Arg, - # Ser, Lys, His, Ala, Gly, Ile, or Leu"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 93                                                    #/note= "Xaa at position 93 is Thr,                                                          Asp, Ser, - # Asn, Pro, Ala, Leu, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 94                                                    #/note= "Xaa at position 94 is Arg,                                                          Ile, Ser, - # Glu, Leu, Val, Gln, Lys, His, Ala, or Pro"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is His,                                                          Gln, Pro, - # Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala      - #,                                                                                         Trp, Phe, - # Ile, or Tyr"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 96                                                    #/note= "Xaa at position 96 is Pro,                                                          Lys, Tyr, - # Gly, Ile, or Thr"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 97                                                    #/note= "Xaa at position 97 is Ile,                                                          Val, Lys, - # Ala, or Asn"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is His,                                                          Ile, Asn, - # Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met      - #,                                                                                         Val, Lys, - # Arg, Tyr, or Pro"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 99                                                    #/note= "Xaa at position 99 is Ile,                                                          Leu, Arg, - # Asp, Val, Pro, Gln, Gly, Ser, Phe,                              or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is:                                                             Lys, Tyr, - # Leu, His, Arg, Ile, Ser, Gln, or Pro"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 101                                                   #/note= "Xaa at position 101 is:                                                             Asp, Pro, - # Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser      - #,                                                                                         Ala, Gly, - # Ile, Leu, or Gln"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 102                                                   #/note= "Xaa at position 102 is Gly,                                                         Leu, Glu, - # Lys, Ser, Tyr, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 103                                                   #/note= "Xaa at position 103 is Asp,                                                         or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 104                                                   #/note= "Xaa at position 104 is:                                                             Trp, Val, - # Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys, Ala      - #,                                                                          #Gly"          Phe, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 105                                                   #/note= "Xaa at position 105 is:                                                             Asn, Pro, - # Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys, Ile      - #,                                                                          #His"          Asp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Glu,                                                         Ser, Ala, - # Lys, Thr, Ile, Gly, or Pro"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 108                                                   #/note= "Xaa at position 108 is Arg,                                                         Lys, Asp, - # Leu, Thr, Ile, Gln, His, Ser, Ala, or Pro"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Arg,                                                         Thr, Pro, - # Glu, Tyr, Leu, Ser, or Gly"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 110                                                   #/note= "Xaa at position 110 is Lys,                                                         Ala, Asn, - # Thr, Leu, Arg, Gln, His, Glu, Ser, Ala,                         or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 111                                                   #/note= "Xaa at position 111 is Leu,                                                         Ile, Arg, - # Asp, or Met"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 112                                                   #/note= "Xaa at position 112 is Thr,                                                         Val, Gln, - # Tyr, Glu, His, Ser, or Phe"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 113                                                   #/note= "Xaa at position 113 is Phe,                                                         Ser, Cys, - # His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val      - #,                                                                                         or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 114                                                   #/note= "Xaa at position 114 is Tyr,                                                         Cys, His, - # Ser, Trp, Arg, or Leu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 115                                                   #/note= "Xaa at position 115 is:                                                             Leu, Asn, - # Val, Pro, Arg, Ala, His, Thr, Trp, or                           Met"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 116                                                   #/note= "Xaa at position 116 is Lys,                                                         Leu, Pro, - # Thr, Met, Asp, Val, Glu, Arg, Trp, Ser,                         Asn, His, - # Ala, Tyr, Phe, Gln, or Ile"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 117                                                   #/note= "Xaa at position 117 is Thr,                                                         Ser, Asn, - # Ile, Trp, Lys, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 118                                                   #/note= "Xaa at position 118 is Leu,                                                         Ser, Pro, - # Ala, Glu, Cys, Asp, or Tyr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 119                                                   #/note= "Xaa at position 119 is Glu,                                                         Ser, Lys, - # Pro, Leu, Thr, Tyr, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 120                                                   #/note= "Xaa at position 120 is Asn,                                                         Ala, Pro, - # Leu, His, Val, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 121                                                   #/note= "Xaa at position 121 is Ala,                                                         Ser, Ile, - # Asn, Pro, Lys, Asp, or Gly"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 122                                                   #/note= "Xaa at position 122 is:                                                             Gln, Ser, - # Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,                         or  Cy - #s"                                                   -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 123                                                   #/note= "Xaa at position 123 is Ala,                                                         Met, Glu, - # His, Ser, Pro, Tyr, or Leu"                      -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 - Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Th - #r Ser Trp Val Asn Cys         #                15                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #            30                                                               - Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #        45                                                                   - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #    60                                                                       - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #80                                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #                95                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ph - #e Xaa Xaa Xaa Xaa Xaa         #           110                                                               - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Gln Gln Thr Thr Leu         #       125                                                                   - Ser Leu Ala Ile Phe                                                             130                                                                       - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 133 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- may or may not precede                                                         the amino - # acid in position 1"                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 17                                                    #/note= "Xaa at position 17 is Ser,                                                          Gly, Asp, - # Met, or Gln"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Asn,                                           #Ile"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 19                                                    #/note= "Xaa at position 19 is Met                                                           or Ile"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 21                                                    #/note="Xaa at position 21 is Asp                                                            or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Ile,                                                          Ala, Leu, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Ile,                                           #Leu"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 25                                                    #/note= "Xaa at position 25 is Thr,                                                          His, Gln, - # or Ala"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 26                                                    #/note= "Xaa at position 26 is His                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 29                                                    #/note= "Xaa at position 29 is Gln,                                           #Val"          Asn, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 30                                                    #/note= "Xaa at position 30 is Pro,                                           #Gln"          Gly, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Pro,                                                          Asp, Gly, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Leu,                                                          Arg, Gln, - # Asn, Gly, Ala, or Glu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 33                                                    #/note= "Xaa at position 33 is Pro                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 34                                                    #/note= "Xaa at position 34 is Leu,                                                          Val, Gly, - # Ser, Lys, Ala, Arg, Gln, Glu, Ile, Phe,          #Met"          Thr, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 35                                                    #/note= "Xaa at position 35 is Leu,                                                          Ala, Asn, - # Pro, Gln, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Phe,                                                          Ser, Pro, - # or Trp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 38                                                    #/note="Xaa at position 38 is Asn                                                            or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Gly,                                                          Asp, Ser, - # Cys, Ala, Asn, Ile, Leu, Met, Tyr,                              or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 44                                                    #/note="Xaa at position 44 is Asp                                                            or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Gln,                                                          Val, Met, - # Leu, Thr, Ala, Asn, Glu, Ser, or Lys"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Asp,                                                          Phe, Ser, - # Thr, Ala, Asn, Gln, Glu, His, Ile,                              Lys, Tyr, - # Val, or Cys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Glu,                                                          Ala, Asn, - # Ser, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Asn,                                                          Arg, Met, - # Pro, Ser, Thr, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 54                                                    #/note="Xaa at position 54 is Arg                                                            or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Arg,                                                          Thr, Val, - # Leu, or Gly"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 56                                                    #/note= "Xaa at position 56 is Pro,                                                          Gly, Ser, - # Gln, Ala, Arg, Asn, Glu, Leu, Thr, Val,                         or Lys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 60                                                    #/note= "Xaa at position 60 is Ala                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Asn,                                                          Pro, Thr, - # or Ile"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Arg                                                           or Lys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 64                                                    #/note= "Xaa at position 64 is Ala                                                           or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Val                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 66                                                    #/note= "Xaa at position 66 is Lys                                                           or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Ser                                            #His"          Phe or                                                         -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Ile, Phe, - # or His"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Gln,                                                          Ala, Pro, - # Thr, Glu, Arg, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 71                                                    #/note= "Xaa at position 71 is Ala,                                           #Arg"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 72                                                    #/note= "Xaa at position 72 is Ser,                                                          Glu, Arg, - # or Asp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Ala                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 76                                                    #/note= "Xaa at position 76 is Ser,                                                          Val, Ala, - # Asn, Glu, Pro, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 isN:                                                             Lys, Thr, - # Gly, Asn, Met, Arg, Ile, Gly, or Asp"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 80                                                    #/note= "Xaa at position 80 is Asn,                                                          Gly, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Leu,                                                          Gln, Trp, - # Arg, Asp, Ala, Asn, Glu, His, Ile,                              Met, Phe, - # Ser, Thr, Tyr, or Val"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 83                                                    #/note= "Xaa at position 83 is Pro                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 is Leu                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 88                                                    #/note= "Xaa at position 88 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 93                                                    #/note= "Xaa at position 93 is Thr,                                                          Asp, Ser, - # Pro, Ala, Leu, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is His,                                                          Pro, Arg, - # Val, Leu, Gly, Asn, Phe, Ser, or Thr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 96                                                    #/note= "Xaa at position 96 is Pro                                                           or Tyr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 97                                                    #/note= "Xaa at position 97 is Ile                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is His,                                                          Ile, Asn, - # Leu, Ala, Thr, Arg, Gln, Lys,                                   Met, Ser, - # Tyr, Val, or Pro"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 99                                                    #/note= "Xaa at position 99 is Ile,                                           #Val"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is Lys,                                                         Arg, Ile, - # Gln, Pro, or Ser"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 101                                                   #/note= "Xaa at position 101 is Asp,                                                         Pro, Met, - # Lys, Thr, His, Asn, Ile, Leu, or Tyr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 104                                                   #/note= "Xaa at position 104 is Trp                                                          or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 105                                                   #/note= "Xaa at position 105 is:                                                             Asn, Pro, - # Ala, Ser, Trp, Gln, Tyr, Leu, Lys, Ile,          #His"          Asp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Glu                                                          or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 108                                                   #/note="Xaa at position 108 is Arg,                                           #Ser"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Arg,                                                         Thr, Glu, - # Leu, or Ser"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 112                                                   #/note= "Xaa at position 112 is Thr,                                          #Gln"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 114                                                   #/note= "Xaa at position 114 is Tyr                                                          or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 115                                                   #/note= "Xaa at position 115 is Leu                                                          or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 116                                                   #/note= "Xaa at position 116 is Lys,                                                         Thr, Val, - # Trp, Ser, Ala, His, Met, Phe, Tyr, or Ile"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 117                                                   #/note= "Xaa at position 117 is Thr                                                          or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 120                                                   #/note= "Xaa at position 120 is Asn,                                                         Pro, Leu, - # His, Val, or Gln"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 121                                                   #/note= "Xaa at position 121 is Ala,                                                         Ser, Ile, - # Asn, Pro, Asp, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 122                                                   #/note= "Xaa at position 122 is:                                                             Gln, Ser, - # Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,                         or Cys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 123                                                   #/note= "Xaa at position 123 is Ala,                                                         Met, Glu, - # His, Ser, Pro, Tyr, or Leu"                      -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 - Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Th - #r Ser Trp Val Asn Cys         #                15                                                           - Xaa Xaa Xaa Ile Xaa Glu Xaa Xaa Xaa Xaa Le - #u Lys Xaa Xaa Xaa Xaa         #            30                                                               - Xaa Xaa Xaa Asp Xaa Xaa Asn Leu Asn Xaa Gl - #u Xaa Xaa Xaa Ile Leu         #        45                                                                   - Met Xaa Xaa Asn Leu Xaa Xaa Xaa Asn Leu Gl - #u Xaa Phe Xaa Xaa Xaa         #    60                                                                       - Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Ile Gl - #u Xaa Xaa Leu Xaa Xaa         #80                                                                           - Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Thr Ala Xa - #a Pro Xaa Arg Xaa Xaa         #                95                                                           - Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa Xaa Xaa Ph - #e Xaa Xaa Lys Leu Xaa         #           110                                                               - Phe Xaa Xaa Xaa Xaa Leu Glu Xaa Xaa Xaa Xa - #a Gln Gln Thr Thr Leu         #       125                                                                   - Ser Leu Ala Ile Phe                                                             130                                                                       - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 133 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- may or may not precede                                                         the amino - # acid in position 1"                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 17                                                    #/note= "Xaa at position 17 is Ser,                                                          Gly, Asp, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Asn,                                           #Ile"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Ile,                                                          Ala, Leu, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 25                                                    #/note= "Xaa at position 25 is Thr,                                           #Gln"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 26                                                    #/note= "Xaa at position 26 is His                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 29                                                    #/note="Xaa at position 29 is Gln                                                            or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 30                                                    #/note= "Xaa at position 30 is Pro                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Leu,                                                          Arg, Asn, - # or Ala"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 34                                                    #/note= "Xaa at position 34 is Leu,                                                          Val, Ser, - # Ala, Arg, Gln, Glu, Ile, Phe, Thr, or Met"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 35                                                    #/note= "Xaa at position 35 is Leu,                                                          Ala, Asn, - # or Pro"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 38                                                    #/note= "Xaa at position 38 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Gly,                                                          Asp, Ser, - # Ala, Asn, Ile, Leu, Met, Tyr, or Arg"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Gln,                                                          Val, Met, - # Leu, Ala, Asn, Glu, or Lys"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Asp,                                                          Phe, Ser, - # Gln, Glu, His, Val, or Thr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Glu,                                                          Asn, Ser, - # or Asp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Asn,                                                          Arg, Pro, - # Thr, or His"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Arg,                                           #Gly"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 56                                                    #/note= "Xaa at position 56 is Pro,                                                          Gly, Ser, - # Ala, Asn, Val, Leu, or Gln"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Asn,                                           #Thr"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 64                                                    #/note= "Xaa at position 64 is Ala                                                           or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Val                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Ser                                                           or Phe"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu                                                           or Phe"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Gln,                                                          Ala, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 76                                                    #/note= "Xaa at position 76 is Ser,                                                          Val, Asn, - # Pro, or Gly"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Lys,                                                          Asn, Met, - # Arg, Ile, or Gly"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 80                                                    #/note= "Xaa at position 80 is Asn,                                                          Gly, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Leu,                                                          Gln, Trp, - # Arg, Asp, Asn, Glu, His, Met, Phe, Ser,                         Thr, Tyr, - # or Val"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 88                                                    #/note= "Xaa at position 88 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 93                                                    #/note= "Xaa at position 93 is Thr,                                           #Ala"          Asp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is His,                                                          Pro, Arg, - # Val, Gly, Asn, Ser, or Thr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is His,                                                          Ile, Asn, - # Ala, Thr, Gln, Glu, Lys, Met, Ser, Tyr,          #Leu"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 99                                                    #/note= "Xaa at position 99 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is Lys                                                          or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION:  101                                                  #/note= "Xaa at position 101 is Asp,                                                         Pro, Met, - # Lys, Thr, His, Asn, Ile, Leu, or Tyr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 105                                                   #/note= "Xaa at position 105 is Asn,                                                         Pro, Ser, - # Ile, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY:  Modified - #-site                                              (B) LOCATION:  108                                                  # /note= "Xaa at position 108 is Arg, Ala,                                                   or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Arg,                                                         Thr, Glu, - # Leu, or Ser"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 112                                                   #/note= "Xaa at position 112 is Thr                                                          or Gln"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 116                                                   #/note= "Xaa at position 116 is Lys,                                                         Val, Trp, - # Ala, His, Phe, Tyr, or Ile"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 117                                                   #/note= "Xaa at position 117 is Thr                                                          or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 120                                                   #/note= "Xaa at position 120 is Asn,                                                         Pro, Leu, - # His, Val, or Gln"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 121                                                   #/note= "Xaa at position 121 is Ala,                                                         Ser, Ile, - # Pro, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 122                                                   #/note= "Xaa at position 122 is Gln,                                                         Met, Trp, - # Phe, Pro, His, Ile, or Tyr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 123                                                   #/note= "Xaa at position 123 is Ala,                                                         Met, Glu, - # Ser, or Leu"                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 - Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Th - #r Ser Trp Val Asn Cys         #                15                                                           - Xaa Xaa Met Ile Asp Glu Xaa Ile Xaa Xaa Le - #u Lys Xaa Xaa Pro Xaa         #            30                                                               - Pro Xaa Xaa Asp Phe Xaa Asn Leu Asn Xaa Gl - #u Asp Xaa Xaa Ile Leu         #        45                                                                   - Met Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Gl - #u Ala Phe Xaa Arg Xaa         #    60                                                                       - Xaa Lys Xaa Xaa Xaa Asn Ala Ser Ala Ile Gl - #u Xaa Xaa Leu Xaa Xaa         #80                                                                           - Leu Xaa Pro Cys Leu Pro Xaa Xaa Thr Ala Xa - #a Pro Xaa Arg Xaa Pro         #                95                                                           - Ile Xaa Xaa Xaa Xaa Gly Asp Trp Xaa Glu Ph - #e Xaa Xaa Lys Leu Xaa         #           110                                                               - Phe Tyr Leu Xaa Xaa Leu Glu Xaa Xaa Xaa Xa - #a Gln Gln Thr Thr Leu         #       125                                                                   - Ser Leu Ala Ile Phe                                                             130                                                                       - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- or Met-Ala- may or may                                                         not prece - #de the amino acid in position 1"                  -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3 is Ser,                                                           Lys, Gly, - # Asp, Met, Gln, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4 is Asn,                                                           His, Leu, - # Ile, Phe, Arg, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5 is Met,                                                           Phe, Ile, - # Arg, Gly, Ala, or Cys"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6 is Ile,                                                           Cys, Gln, - # Glu, Arg, Pro, or Ala"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7 is Asp,                                                           Phe, Lys, - # Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser,                         or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8 is Glu,                                                           Trp, Pro, - # Ser, Ala, His, Asp, Asn, Gln, Leu, Val,                         or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9 isON:                                                             Ile, Val, - # Ala, Leu, Gly, Trp, Lys, Phe, Leu, Ser                          or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                    #/note= "Xaa at position 10 is Ile,                                                          Gly, Val, - # Arg, Ser, Phe, or Leu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa at position 11 is Thr,                                                          His, Gly, - # Gln, Arg, Pro, or Ala"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa at position 12 is His,                                                          Thr, Phe, - # Gly, Arg, Ala, or Trp"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 13                                                    #/note= "Xaa at position 13 is Leu,                                                          Gly, Arg, - # Thr, Ser, or Ala"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa at position 14 is Lys,                                                          Arg, Leu, - # Gln, Gly, Pro, Val, or Trp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa at position 15 is Gln,                                                          Asn, Leu, - # Pro, Arg, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa at position 16 is Pro,                                                          His, Thr, - # Gly, Asp, Gln, Ser, Leu, or Lys"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 17                                                    #/note= "Xaa at position 17 is Pro,                                                          Asp, Gly, - # Ala, Arg, Leu, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Leu,                                                          Val, Arg, - # Gln, Asn, Gly, Ala, or Glu"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 19                                                    #/note= "Xaa at position 19 is Pro,                                                          Leu, Gln, - # Ala, Thr, or Glu"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Leu,                                                          Val, Gly, - # Ser, Lys, Glu, Gln, Thr, Arg, Ala, Phe,          #Met"          Ile, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 21                                                    #/note= "Xaa at position 21 is Leu,                                                          Ala, Gly, - # Asn, Pro, Gln, or Val"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 22                                                    #/note= "Xaa at position 22 is Asp,                                           #Val"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Phe,                                                          Ser, Pro, - # Trp, or Ile"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 26                                                    #/note= "Xaa at position 26 is Leu,                                           #Arg"          Trp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 27                                                    #/note= "Xaa at position 27 is Asn,                                                          Cys, Arg, - # Leu, His, Met, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 28                                                    #/note= "Xaa at position 28 is Gly,                                                          Asp, Ser, - # Cys, Ala, Lys, Asn, Thr, Leu, Val, Glu,                         Phe, Tyr, - # Ile, or Met"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 29                                                    #/note= "Xaa at position 29 is Glu,                                                          Asn, Tyr, - # Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr,          #Ser"          Gly, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 30                                                    #/note= "Xaa at position 30 is Asp,                                                          Ser, Leu, - # Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln,          #Pro"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Gln,                                                          Pro, Phe, - # Val, Met, Leu, Thr, Lys, Asp, Asn, Arg,                         Ser, Ala, - # Ile, Glu, His, or Trp"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Asp,                                                          Phe, Ser, - # Thr, Cys, Glu, Asn, Gln, Lys, His, Ala,                         Tyr, Ile, - # Val, or Gly"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 33                                                    #/note= "Xaa at position 33 is Ile,                                                          Gly, Val, - # Ser, Arg, Pro, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 34                                                    #/note= "Xaa at position 34 is Leu,                                                          Ser, Cys, - # Arg, Ile, His, Phe, Glu, Lys, Thr, Ala,                         Met, Val, - # or Asn"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 35                                                    #/note= "Xaa at position 35 is Met,                                                          Arg, Ala, - # Gly, Pro, Asn, His, or Asp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 36                                                    #/note= "Xaa at position 36 is Glu,                                                          Leu, Thr, - # Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val,                         His, Phe, - # Met, or Gln"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Asn,                                                          Arg, Met, - # Pro, Ser, Thr, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 38                                                    #/note= "Xaa at position 38 is Asn,                                                          His, Arg, - # Leu, Gly, Ser, or Thr"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 39                                                    #/note= "Xaa at position 39 isN:                                                             Leu, Thr, - # Ala, Gly, Glu, Pro, Lys, Ser, or Met"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 40                                                    #/note= "Xaa at position 40 is Arg,                                                          Asp, Ile, - # Ser, Val, Thr, Gln, Asn, Lys, His,               #Leu"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 41                                                    #/note= "Xaa at position 41 is Arg,                                                          Thr, Val, - # Ser, Leu, or Gly"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Pro,                                                          Gly, Cys, - # Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr,                         Phe, Leu, - # Val, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 43                                                    #/note= "Xaa at position 43 is Asn                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 44                                                    #/note= "Xaa at position 44 is Leu,                                                          Ser, Asp, - # Arg, Gln, Val, or Cys"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Glu,                                                          Tyr, His, - # Leu, Pro, or Arg"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Ala,                                                          Ser, Pro, - # Tyr, Asn, or Thr"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 47                                                    #/note= "Xaa at position 47 is Phe,                                                          Asn, Glu, - # Pro, Lys, Arg, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 48                                                    #/note= "Xaa at position 48 is Asn,                                                          His, Val, - # Arg, Pro, Thr, Asp, or Ile"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 49                                                    #/note= "Xaa at position 49 is Arg,                                                          Tyr, Trp, - # Lys, Ser, His, Pro, or Val"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Ala,                                                          Asn, Pro, - # Ser, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Val,                                                          Thr, Pro, - # His, Leu, Phe, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 52                                                    #/note= "Xaa at position 52 is Lys,                                                          Ile, Arg, - # Val, Asn, Glu, or Ser"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 53                                                    #/note= "Xaa at position 53 is Ser,                                                          Ala, Phe, - # Val, Gly, Asn, Ile, Pro, or His"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 54                                                    #/note= "Xaa at position 54 is Leu,                                                          Val, Trp, - # Ser, Ile, Phe, Thr, or His"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Gln,                                                          Ala, Pro, - # Thr, Glu, Arg, Trp, Gly, or Leu"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 56                                                    #/note= "Xaa at position 56 is Asn,                                                          Leu, Val, - # Trp, Pro, or Ala"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 57                                                    #/note= "Xaa at position 57 is Ala,                                                          Met, Leu, - # Pro, Arg, Glu, Thr, Gln, Trp, or Asn"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 58                                                    #/note= "Xaa at position 58 is Ser,                                                          Glu, Met, - # Ala, His, Asn, Arg, or Asp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 59                                                    #/note= "Xaa at position 59 is Ala,                                                          Glu, Asp, - # Leu, Ser, Gly, Thr, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 60                                                    #/note= "Xaa at position 60 is Ile,                                                          Met, Thr, - # Pro, Arg, Gly, Ala"                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 61                                                    #/note= "Xaa at position 61 isN:                                                             Glu, Lys, - # Gly, Asp, Pro, Trp, Arg, Ser, Gln,                              or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Ser,                                                          Val, Ala, - # Asn, Trp, Glu, Pro, Gly, or Asp"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Ile,                                                          Ser, Arg, - # Thr, or Leu"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 64                                                    #/note= "Xaa at position 64 is Leu,                                                          Ala, Ser, - # Glu, Phe, Gly, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Lys,                                                          Thr, Gly, - # Asn, Met, Arg, Ile, or Asp"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 66                                                    #/note= "Xaa at position 66 is Asn,                                                          Trp, Val, - # Gly, Thr, Leu, Glu, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Leu,                                                          Gln, Gly, - # Ala, Trp, Arg, Val, or Lys"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Gln, Lys, - # Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala      - #,                                                                                         Tyr, Phe, - # Ile, Met, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Pro,                                                          Ala, Thr, - # Trp, Arg, or Met"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 70                                                    #/note= "Xaa at position 70 is Cys,                                                          Glu, Gly, - # Arg, Met, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 71                                                    #/note= "Xaa at position 71 is Leu,                                                          Asn, Val, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 72                                                    #/note= "Xaa at position 72 is Pro,                                                          Cys, Arg, - # Ala, or Lys"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Leu,                                                          Ser, Trp, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 74                                                    #/note= "Xaa at position 74 is Ala,                                                          Lys, Arg, - # Val, or Trp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 75                                                    #/note= "Xaa at position 75 is Thr,                                                          Asp, Cys, - # Leu, Val, Glu, His, Asn, or Ser"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 76                                                    #/note= "Xaa at position 76 is Ala,                                                          Pro, Ser, - # Thr, Gly, Asp, Ile, or Met"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ala,                                                          Pro, Ser, - # Thr, Phe, Leu, Asp, or His"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 78                                                    #/note= "Xaa at position 78 is Pro,                                                          Phe, Arg, - # Ser, Lys, His, Ala, Gly, Ile, or Leu"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Thr,                                                          Asp, Ser, - # Asn, Pro, Ala, Leu, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 80                                                    #/note= "Xaa at position 80 is Arg,                                                          Ile, Ser, - # Glu, Leu, Val, Gln, Lys, His, Ala, or Pro"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 81                                                    #/note= "Xaa at position 81 is His,                                                          Gln, Pro, - # Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser,                         Ala, Trp, - # Phe, Ile, or Tyr"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Pro,                                                          Lys, Tyr, - # Gly, Ile, or Thr"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 83                                                    #/note= "Xaa at position 83 is Ile,                                                          Val, Lys, - # Ala, or Asn"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 84                                                    #/note= "Xaa at position 84 is His,                                                          Ile, Asn, - # Leu, Asp, Ala, Thr, Glu, Gln, Ser,                              Phe, Met, - # Val, Lys, Arg, Tyr, or Pro"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 isN:                                                             Ile, Leu, - # Arg, Asp, Val, Pro, Gln, Gly, Ser,               #His"          Phe, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 86                                                    #/note= "Xaa at position 86 isN:                                                             Lys, Tyr, - # Leu, His, Arg, Ile, Ser, Gln, or Pro"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 isN:                                                             Asp, Pro, - # Met, Lys, His, Thr, Val, Tyr, Glu, Asn,                         Ser, Ala, - # Gly, Ile, Leu, or Gln"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 88                                                    #/note= "Xaa at position 88 Gly,                                                             Leu, Glu, - # Lys, Ser, Tyr, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 89                                                    #/note= "Xaa at position 89 is Asp                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 90                                                    #/note= "Xaa at position 90 isN:                                                             Trp, Val, - # Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,                         Ala, Phe, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 isN:                                                             Asn, Pro, - # Ala, Phe, Ser, Trp, Gln, Tyr, Leu, Lys,                         Ile, Asp, - # or His"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 92                                                    #/note= "Xaa at position 92 is Glu,                                                          Ser, Ala, - # Lys, Thr, Ile, Gly, or Pro"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 94                                                    #/note= "Xaa at position 94 is Arg,                                                          Lys, Asp, - # Leu, Thr, Ile, Gln, His, Ser, Ala, or Pro"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is Arg,                                                          Thr, Pro, - # Glu, Tyr, Leu, Ser, or Gly"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 96                                                    #/note= "Xaa at position 96 is Lys,                                                          Asn, Thr, - # Leu, Gln, Arg, His, Glu, Ser, Ala,                              or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 97                                                    #/note= "Xaa at position 97 is Leu,                                                          Ile, Arg, - # Asp, or Met"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is Thr,                                                          Val, Gln, - # Tyr, Glu, His, Ser, or Phe"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 99                                                    #/note= "Xaa at position 99 is Phe,                                                          Ser, Cys, - # His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile,          #Asn"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is Tyr,                                                         Cys, His, - # Ser, Trp, Arg, or Leu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 101                                                   #/note= "Xaa at position 101 is Leu,                                                         Asn, Val, - # Pro, Arg, Ala, His, Thr, Trp, or Met"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 102                                                   #/note= "Xaa at position 102 is:                                                             Lys, Leu, - # Pro, Thr, Met, Asp, Val, Glu, Arg, Trp,                         Ser, Asn, - # His, Ala, Tyr, Phe, Gln, or Ile"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 103                                                   #/note= "Xaa at position 103 is Thr,                                                         Ser, Asn, - # Ile, Trp, Lys, or Pro"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 104                                                   #/note= "Xaa at position 104 is Leu,                                                         Ser, Pro, - # Ala, Glu, Cys, Asp, or Tyr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 105                                                   #/note= "Xaa at position 105 is Glu,                                                         Ser, Lys, - # Pro, Leu, Thr, Tyr, or Arg"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Asn,                                                         Ala, Pro, - # Leu, His, Val or Gln"                            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 107                                                   #/note= "Xaa at position 107 is Ala,                                                         Ser, Ile, - # Asn, Pro, Lys, Asp, or Gly"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 108                                                   #/note= "Xaa at position 108 is:                                                             Gln, Ser, - # Met, Trp, Arg, Phe, Pro, His, Ile, Tyr,                         or Cys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Ala,                                                         Met, Glu, - # His, Ser, Pro, Tyr, or Leu"                      -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 - Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #                15                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #            30                                                               - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #        45                                                                   - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #    60                                                                       - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Xaa Xaa Xaa         #80                                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Phe Xaa Xaa Xaa         #                95                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xa - #a Xaa Xaa Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- or Met-Ala- may or may                                                         not prece - #de the amino acid in position 1"                  -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3 is Ser,                                                           Gly, Asp, - # Met, or Gln"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4 is Asn,                                            #Ile"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5 is Met                                                            or Ile"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7 is Asp or                                                         Glu"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9 is Ile,                                                           Ala, Leu, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                    #/note= "Xaa at position 10 is Ile,                                           #Leu"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa at position 11 is Thr,                                                          His, Gln, - # or Ala"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa at position 12 is His                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa at position 15 is Gln,                                           #Val"          Asn, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa at position 16 is Pro,                                           #Gln"          Gly, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 17                                                    #/note= "Xaa at position 17 is Pro,                                                          Asp, Gly, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Leu,                                                          Arg, Gln, - # Asn, Gly, Ala, or Glu"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 19                                                    #/note= "Xaa at position 19 is Pro                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Leu,                                                          Val, Gly, - # Ser, Lys, Ala, Arg, Gln, Glu, Ile, Phe,          #Met"          Thr, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 21                                                    #/note= "Xaa at position 21 is Leu,                                                          Ala, Asn, - # Pro, Gln, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Phe,                                                          Ser, Pro, - # or Trp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 28                                                    #/note= "Xaa at position 28 is Gly,                                                          Asp, Ser, - # Cys, Ala, Asn, Ile, Leu, Met, Tyr, or Arg"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 30                                                    #/note= "Xaa at position 30 is Asp                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Gln,                                                          Val, Met, - # Leu, Thr, Ala, Asn, Glu, Ser, or Lys"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Asp,                                                          Phe, Ser, - # Thr, Ala, Asn, Gln, Glu, His, Ile, Lys,                         Tyr, Val, - # or Cys"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 36                                                    #/note= "Xaa at position 36 is Glu,                                                          Ala, Asn, - # Ser, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Asn,                                                          Arg, Met, - # Pro, Ser, Thr, or His"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 40                                                    #/note= "Xaa at position 40 is Arg                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 41                                                    #/note= "Xaa at position 41 is Arg,                                                          Thr, Val, - # Leu, or Gly"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Pro,                                                          Gly, Ser, - # Gln, Ala, Arg, Asn, Glu, Leu, Thr, Val,                         or Lys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Ala                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 48                                                    #/note= "Xaa at position 48 is Asn,                                                          Pro, Thr, - # or Ile"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 49                                                    #/note= "Xaa at position 49 is Arg                                                           or Lys"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Ala                                                           or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Val                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 52                                                    #/note= "Xaa at position 52 is Lys                                                           or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 53                                                    #/note= "Xaa at position 53 is Ser,                                           #His"          Phe, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 54                                                    #/note= "Xaa at position 54 is Leu,                                                          Ile, Phe, - # or His"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Gln,                                                          Ala, Pro, - # Thr, Glu, Arg, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 57                                                    #/note= "Xaa at position 57 is Ala,                                           #Arg"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 58                                                    #/note= "Xaa at position 58 is Ser,                                                          Glu, Arg, - # or Asp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 59                                                    #/note= "Xaa at position 59 is Ala                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Ser,                                                          Val, Ala, - # Asn, Glu, Pro, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Lys,                                                          Thr, Gly, - # Asn, Met, Arg, Ile, Gly, or Asp"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 66                                                    #/note= "Xaa at position 66 is Asn,                                                          Gly, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Gln, Trp, - # Arg, Asp, Ala, Asn, Glu, His, Ile, Met,                         Phe, Ser, - # Thr, Tyr, or Val"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Pro                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 71                                                    #/note= "Xaa at position 71 is Leu                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 74                                                    #/note= "Xaa at position 74 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Thr,                                                          Asp, Ser, - # Pro, Ala, Leu, or Arg"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 81                                                    #/note= "Xaa at position 81 is His,                                                          Pro, Arg, - # Val, Leu, Gly, Asn, Phe, Ser, or Thr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Pro                                                           or Tyr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 83                                                    #/note= "Xaa at position 83 is Ile                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 84                                                    #/note= "Xaa at position 84 is His,                                                          Ile, Asn, - # Leu, Ala, Thr, Arg, Gln, Lys,                                   Met, Ser, - # Tyr, Val, or Pro"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 is Ile,                                           #Val"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 86                                                    #/note= "Xaa at position 86 is Lys,                                                          Arg, Ile, - # Gln, Pro, or Ser"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Asp,                                                          Pro, Met, - # Lys, His, Thr, Asn, Ile, Leu, or Tyr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 90                                                    #/note= "Xaa at position 90 is Trp                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note="Xaa at position 91 is Asn,                                                           Pro, Ala, - # Ser, Trp, Gln, Tyr, Leu, Lys, Ile, Asp,                         or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 92                                                    #/note= "Xaa at position 92 is Glu                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 94                                                    #/note= "Xaa at position 94 is Arg,                                           #Ser"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is Arg,                                                          Thr, Glu, - # Leu, or Ser"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is Thr,                                           #Gln"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is Tyr                                                          or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 101                                                   #/note= "Xaa at position 101 is Leu                                                          or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 102                                                   #/note= "Xaa at position 102 is Lys,                                                         Thr, Val, - # Trp, Ser, Ala, His, Met, Phe, Tyr, or Ile"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 103                                                   #/note= "Xaa at position 103 is Thr                                                          or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Asn,                                                         Pro, Leu, - # His, Val, or Gln"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 107                                                   #/note= "Xaa at position 107 is Ala,                                                         Ser, Ile, - # Asn, Pro, Asp, or Gly"                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 108                                                   #/note= "Xaa at position 108 is Gln,                                                         Ser, Met, - # Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Ala,                                                         Met, Glu, - # His, Ser, Pro, Tyr, or Leu"                      -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 - Asn Cys Xaa Xaa Xaa Ile Xaa Glu Xaa Xaa Xa - #a Xaa Leu Lys Xaa Xaa         #                15                                                           - Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Asn Leu As - #n Xaa Glu Xaa Xaa Xaa         #            30                                                               - Ile Leu Met Xaa Xaa Asn Leu Xaa Xaa Xaa As - #n Leu Glu Xaa Phe Xaa         #        45                                                                   - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xa - #a Ile Glu Xaa Xaa Leu         #    60                                                                       - Xaa Xaa Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Th - #r Ala Xaa Pro Xaa Arg         #80                                                                           - Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa Xa - #a Xaa Phe Xaa Xaa Lys         #                95                                                           - Leu Xaa Phe Xaa Xaa Xaa Xaa Leu Glu Xaa Xa - #a Xaa Xaa Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- or Met-Ala- may or may                                                         not prece - #de the amino acid in position 1"                  -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3 is Ser,                                                           Gly, Asp, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4 is Asn,                                            #Ile"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9 is Ile,                                                           Ala, Leu, - # or Gly"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa at position 11 is Thr,                                           #Gln"          His, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa at position 12 is His                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa at position 15 is Gln                                                           or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa at position 16 is Pro                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Leu,                                                          Arg, Asn, - # or Ala"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Leu,                                                          Val, Ser, - # Ala, Arg, Gln, Glu, Ile, Phe, Thr, or Met"       -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 21                                                    #/note= "Xaa at position 21 is Leu,                                                          Ala, Asn, - # or Pro"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 28                                                    #/note= "Xaa at position 28 is Gly,                                                          Asp, Ser, - # Ala, Asn, Ile, Leu, Met, Tyr, or Arg"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Gln,                                                          Val, Met, - # Leu, Ala, Asn, Glu, or Lys"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Asp,                                                          Phe, Ser, - # Ala, Gln, Glu, His, Val, or Thr"                 -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 36                                                    #/note= "Xaa at position 36 is Glu,                                                          Asn, Ser, - # or Asp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Asn,                                                          Arg, Pro, - # Thr, or His"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 41                                                    #/note= "Xaa at position 41 is Arg,                                           #Gly"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Pro,                                                          Gly, Ser, - # Ala, Asn, Val, Leu, or Gln"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 48                                                    #/note= "Xaa at position 48 is Asn,                                           #Thr"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Ala                                                           or Asn"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Val                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 53                                                    #/note= "Xaa at position 53 is Ser                                                           or Phe"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 54                                                    #/note= "Xaa at position 54 is Leu                                                           or Phe"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Gln,                                                          Ala, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Ser,                                                          Val, Asn, - # Pro, or Gly"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Lys,                                                          Asn, Met, - # Arg, Ile, or Gly"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 66                                                    #/note= "Xaa at position 66 is Asn,                                                          Gly, Glu, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Gln, Trp, - # Arg, Asp, Asn, Glu, His, Met, Phe, Ser,                         Thr, Tyr, - # or Val"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 74                                                    #/note= "Xaa at position 74 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Thr,                                           #Ala"          Asp, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 81                                                    #/note= "Xaa at position 81 is His,                                                          Pro, Arg, - # Val, Gly, Asn, Ser, or Thr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 84                                                    #/note= "Xaa at position 84 is His,                                                          Ile, Asn, - # Leu, Ala, Thr, Arg, Gln, Glu, Lys, Met,                         Ser, Tyr, - # Val, or Leu"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 is Ile                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 86                                                    #/note= "Xaa at position 86 is Lys                                                           or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Asp,                                                          Pro, Met, - # Lys, His, Pro, Asn, Ile, Leu, or Tyr"            -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Asn,                                                          Pro, Ser, - # Ile, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 94                                                    #/note="Xaa at position 94 is Arg,                                            #Ser"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is Arg,                                                          Thr, Glu, - # Leu, or Ser"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is Thr                                                           or Gln"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 102                                                   #/note= "Xaa at position 102 is Lys,                                                         Val, Trp, - # or Ile"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 103                                                   #/note= "Xaa at position 103 is Thr,                                                         Ala, His, - # Phe, Tyr, or Ser"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Asn,                                                         Pro, Leu, - # His, Val, or Gln"                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 107                                                   #/note= "Xaa at position 107 is Ala,                                                         Ser, Ile, - # Pro, or Asp"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 108                                                   #/note= "Xaa at position 108 is Gln,                                                         Met, Trp, - # Phe, Pro, His, Ile, or Tyr"                      -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Ala,                                                         Met, Glu, - # Ser, or Leu"                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 - Asn Cys Xaa Xaa Met Ile Asp Glu Xaa Ile Xa - #a Xaa Leu Lys Xaa Xaa         #                15                                                           - Pro Xaa Pro Xaa Xaa Asp Phe Xaa Asn Leu As - #n Xaa Glu Asp Xaa Xaa         #            30                                                               - Ile Leu Met Xaa Xaa Asn Leu Arg Xaa Xaa As - #n Leu Glu Ala Phe Xaa         #        45                                                                   - Arg Xaa Xaa Lys Xaa Xaa Xaa Asn Ala Ser Al - #a Ile Glu Xaa Xaa Leu         #    60                                                                       - Xaa Xaa Leu Xaa Pro Cys Leu Pro Xaa Xaa Th - #r Ala Xaa Pro Xaa Arg         #80                                                                           - Xaa Pro Ile Xaa Xaa Xaa Xaa Gly Asp Trp Xa - #a Glu Phe Xaa Xaa Lys         #                95                                                           - Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu Xaa Xa - #a Xaa Xaa Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 133 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- may or may not precede                                                         the amino - # acid in position 1"                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Asn                                                           or Ile"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 19                                                    #/note= "Xaa at position 19 is Met,                                           #Ile"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Ile,                                           #Leu"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Ile,                                           #Leu"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 25                                                    #/note= "Xaa at position 25 is Thr                                                           or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 29                                                    #/note= "Xaa at position 29 is Gln,                                                          Arg, Val, - # or Ile"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Leu,                                                          Ala, Asn, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 34                                                    #/note= "Xaa at position 34 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Phe,                                           #Ser"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION:; 38                                                   #/note= "Xaa at position 38 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Gly,                                                          Ala, Ser, - # Asp, or Asn"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Gln,                                           #Met"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Asp                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 49                                                    #/note= "Xaa at position 49 is Met,                                                          Ile, Leu, - # or Asp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 50                                                    #/note= "Xaa at position 50 is Glu                                                           or Asp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Asn,                                           #Ser"          Arg, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Arg,                                           #Thr"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 56                                                    #/note= "Xaa at position 56 is Pro                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 59                                                    #/note= "Xaa at position 59 is Glu                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 60                                                    #/note= "Xaa at position 60 is Ala                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Asn                                            #Pro"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 63                                                    #/note= "Xaa at position 63 is Arg                                                           or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Val                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Ser,                                                          Asn, His, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 69                                                    #/note= "Xaa at position 69 is Gln                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Ala                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 76                                                    #/note= "Xaa at position 76 is Ser,                                           #Pro"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Lys,                                           #Ser"          Arg, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 82                                                    #/note= "Xaa at position 82 is Leu,                                                          Glu, Val, - # or Trp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 85                                                    #/note= "Xaa at position 85 is Leu                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Leu,                                           #Tyr"          Ser, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 88                                                    #/note= "Xaa at position 88 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 93                                                    #/note= "Xaa at position 93 is Pro                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is His                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is His,                                           #Thr"          Ile, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 100                                                   #/note= "Xaa at position 100 is Lys                                                          or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 101                                                   #/note= "Xaa at position 101 is Asp,                                          #Met"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 105                                                   #/note= "Xaa at position 105 is Asn                                                          or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Arg,                                          #Leu"          Glu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 112                                                   #/note= "Xaa at position 112 is Thr                                                          or Gln"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 116                                                   #/note= "Xaa at position 116 is Lys,                                                         Val, Trp, - # or Ser"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 117                                                   #/note= "Xaa at position 117 is Thr                                                          or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 120                                                   #/note= "Xaa at position 120 is Asn,                                          #His"          Gln, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 123                                                   #/note= "Xaa at position 123 is Ala                                                          or Glu"                                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 - Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Th - #r Ser Trp Val Asn Cys         #                15                                                           - Ser Xaa Xaa Xaa Asp Glu Xaa Ile Xaa His Le - #u Lys Xaa Pro Pro Xaa         #            30                                                               - Pro Xaa Leu Asp Xaa Xaa Asn Leu Asn Xaa Gl - #u Asp Xaa Xaa Ile Leu         #        45                                                                   - Xaa Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Xa - #a Xaa Phe Xaa Xaa Ala         #    60                                                                       - Xaa Lys Xaa Leu Xaa Asn Ala Ser Xaa Ile Gl - #u Xaa Ile Leu Xaa Asn         #80                                                                           - Leu Xaa Pro Cys Xaa Pro Xaa Xaa Thr Ala Xa - #a Pro Xaa Arg Xaa Pro         #                95                                                           - Ile Xaa Ile Xaa Xaa Gly Asp Trp Xaa Glu Ph - #e Arg Xaa Lys Leu Xaa         #           110                                                               - Phe Tyr Leu Xaa Xaa Leu Glu Xaa Ala Gln Xa - #a Gln Gln Thr Thr Leu         #       125                                                                   - Ser Leu Ala Ile Phe                                                             130                                                                       - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Met- or Met-Ala may or may                                                          not prece - #de the amino acid in position 1"                  -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4 is Asn or                                                         Ile"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5 is Met,                                            #Ile"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6 is Ile,                                            #Leu"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9 is Ile,                                            #Leu"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa at position 11 is Thr                                                           or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa at position 15 is Gln,                                                          Arg, Val, - # or Ile"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 18                                                    #/note= "Xaa at position 18 is Leu,                                                          Ala, Asn, - # or Arg"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 20                                                    #/note= "Xaa at position 20 is Leu                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 23                                                    #/note= "Xaa at position 23 is Phe,                                           #Ser"          Pro, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 24                                                    #/note= "Xaa at position 24 is Asn                                                           or Ala"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 28                                                    #/note= "Xaa at position 28 is Gly,                                                          Ala, Ser, - # Asp, or Asn"                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 31                                                    #/note= "Xaa at position 31 is Gln,                                           #Met"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 32                                                    #/note= "Xaa at position 32 is Asp                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 35                                                    #/note= "Xaa at position 35 is Met,                                           #Asp"          Ile, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 36                                                    #/note= "Xaa at position 36 is Glu                                                           or Asp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 37                                                    #/note= "Xaa at position 37 is Asn,                                           #Ser"          Arg, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 41                                                    #/note= "Xaa at position 41 is Arg,                                           #Thr"          Leu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 42                                                    #/note= "Xaa at position 42 is Pro                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 45                                                    #/note= "Xaa at position 45 is Glu                                                           or Leu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 46                                                    #/note= "Xaa at position 46 is Ala                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 48                                                    #/note= "Xaa at position 48 is Asn,                                           #Pro"          Val, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 49                                                    #/note= "Xaa at position 49 is Arg                                                           or His"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 51                                                    #/note= "Xaa at position 51 is Val                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 53                                                    #/note= "Xaa at position 53 is Ser,                                                          Asn, His, - # or Gln"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 55                                                    #/note= "Xaa at position 55 is Gln                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 59                                                    #/note= "Xaa at position 59 is Ala                                                           or Gly"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 62                                                    #/note= "Xaa at position 62 is Ser,                                           #Pro"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 65                                                    #/note= "Xaa at position 65 is Lys,                                           #Ser"          Arg, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 67                                                    #/note= "Xaa at position 67 is Leu,                                           #Val"          Glu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 68                                                    #/note= "Xaa at position 68 is Leu,                                                          Glu, Val, - # or Trp"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 71                                                    #/note= "Xaa at position 71 is Leu                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 73                                                    #/note= "Xaa at position 73 is Leu,                                           #Tyr"          Ser, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 74                                                    #/note= "Xaa at position 74 is Ala                                                           or Trp"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 77                                                    #/note= "Xaa at position 77 is Ala                                                           or Pro"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 79                                                    #/note= "Xaa at position 79 is Pro                                                           or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 81                                                    #/note= "Xaa at position 81 is His                                                           or Thr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 84                                                    #/note= "Xaa at position 84 is His,                                           #Thr"          Ile, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 86                                                    #/note= "Xaa at position 86 is Lys                                                           or Arg"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 87                                                    #/note= "Xaa at position 87 is Asp,                                           #Met"          Ala, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 91                                                    #/note= "Xaa at position 91 is Asn                                                           or Glu"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 95                                                    #/note= "Xaa at position 95 is Arg,                                           #Leu"          Glu, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 98                                                    #/note= "Xaa at position 98 is Thr                                                           or Gln"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 102                                                   #/note= "Xaa at position 102 is Lys,                                                         Val, Trp, - # or Ser"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 103                                                   #/note= "Xaa at position 103 is Thr                                                          or Ser"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 106                                                   #/note= "Xaa at position 106 is Asn,                                          #His"          Gln, or                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 109                                                   #/note= "Xaa at position 109 is Ala                                                          or Glu"                                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 - Asn Cys Ser Xaa Xaa Xaa Asp Glu Xaa Ile Xa - #a His Leu Lys Xaa Pro         #                15                                                           - Pro Xaa Pro Xaa Leu Asp Xaa Xaa Asn Leu As - #n Xaa Glu Asp Xaa Xaa         #            30                                                               - Ile Leu Xaa Xaa Xaa Asn Leu Arg Xaa Xaa As - #n Leu Xaa Xaa Phe Xaa         #        45                                                                   - Xaa Ala Xaa Lys Xaa Leu Xaa Asn Ala Ser Xa - #a Ile Glu Xaa Ile Leu         #    60                                                                       - Xaa Asn Xaa Xaa Pro Cys Xaa Pro Xaa Xaa Th - #r Ala Xaa Pro Xaa Arg         #80                                                                           - Xaa Pro Ile Xaa Ile Xaa Xaa Gly Asp Trp Xa - #a Glu Phe Arg Xaa Lys         #                95                                                           - Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu Xaa Al - #a Gln Xaa Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Arg Pro         #                15                                                           - Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu As - #n Ala Glu Asp Val Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Arg Pro         #                15                                                           - Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu As - #n Ser Glu Asp Met Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Val Pro         #                15                                                           - Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu As - #n Ser Glu Asp Met Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Leu Pro As - #n Leu Leu Ala Phe Val         #        45                                                                   - Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Leu Pro As - #n Leu Glu Ser Phe Val         #        45                                                                   - Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Thr Pro As - #n Leu Leu Ala Phe Val         #        45                                                                   - Arg Ala Val Lys His Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Gl - #y Ile Glu Ala Ile Leu         #    60                                                                       - Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Th - #r Ala Ala Pro Ser Arg         #80                                                                           - His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gl - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Gl - #y Ile Glu Ala Ile Leu         #    60                                                                       - Arg Asn Leu Val Pro Cys Leu Pro Ser Ala Th - #r Ala Ala Pro Ser Arg         #80                                                                           - His Pro Ile Thr Ile Lys Ala Gly Asp Trp Gl - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Glu Lys         #                95                                                           - Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Al - #a Gln Glu Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Glu Lys         #                95                                                           - Leu Thr Phe Tyr Leu Val Ser Leu Glu His Al - #a Gln Glu Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Gl - #y Ile Glu Ala Ile Leu         #    60                                                                       - Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Th - #r Ala Ala Pro Ser Arg         #80                                                                           - His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gl - #n Glu Phe Arg Glu Lys         #                95                                                           - Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Al - #a Gln Glu Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Gl - #y Ile Glu Ala Ile Leu         #    60                                                                       - Arg Asn Leu Val Pro Cys Leu Pro Ser Ala Th - #r Ala Ala Pro Ser Arg         #80                                                                           - His Pro Ile Thr Ile Lys Ala Gly Asp Trp Gl - #n Glu Phe Arg Glu Lys         #                95                                                           - Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Al - #a Gln Glu Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                - Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Th - #r His Leu Lys Gln Pro         #                15                                                           - Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu As - #n Gly Glu Asp Gln Asp         #            30                                                               - Ile Leu Met Glu Asn Asn Leu Arg Arg Pro As - #n Leu Glu Ala Phe Asn         #        45                                                                   - Arg Ala Val Lys Ser Leu Gln Asn Ala Ser Gl - #y Ile Glu Ala Ile Leu         #    60                                                                       - Arg Asn Leu Val Pro Cys Leu Pro Ser Ala Th - #r Ala Ala Pro Ser Arg         #80                                                                           - His Pro Ile Thr Ile Lys Ala Gly Asp Trp Gl - #n Glu Phe Arg Glu Lys         #                95                                                           - Leu Thr Phe Tyr Leu Val Ser Leu Glu His Al - #a Gln Glu Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Arg Pro         #                15                                                           - Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu As - #n Ala Glu Asp Val Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Leu Pro As - #n Leu Glu Ser Phe Val         #        45                                                                   - Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Arg Pro         #                15                                                           - Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu As - #n Ser Glu Asp Met Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Thr Pro As - #n Leu Leu Ala Phe Val         #        45                                                                   - Arg Ala Val Lys His Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 111 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                - Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Hi - #s His Leu Lys Val Pro         #                15                                                           - Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu As - #n Ser Glu Asp Met Asp         #            30                                                               - Ile Leu Met Glu Arg Asn Leu Arg Leu Pro As - #n Leu Leu Ala Phe Val         #        45                                                                   - Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Al - #a Ile Glu Ser Ile Leu         #    60                                                                       - Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Th - #r Ala Ala Pro Thr Arg         #80                                                                           - His Pro Ile His Ile Lys Asp Gly Asp Trp As - #n Glu Phe Arg Arg Lys         #                95                                                           - Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Al - #a Gln Ala Gln Gln             #           110                                                               - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                - Met Ala Asn Cys Ser Asn Met Ile Asp Glu Il - #e Ile Thr His Leu Lys         #                15                                                           - Gln Pro Pro Leu Pro Leu Leu Asp Phe Asn As - #n Leu Asn Gly Glu Asp         #            30                                                               - Gln Asp Ile Leu Met Glu Asn Asn Leu Arg Ar - #g Pro Asn Leu Glu Ala         #        45                                                                   - Phe Asn Arg Ala Val Lys Ser Leu Gln Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                - Met Ala Asn Cys Ser Asn Met Ile Asp Glu Il - #e Ile Thr His Leu Lys         #                15                                                           - Gln Pro Pro Leu Pro Leu Leu Asp Phe Asn As - #n Leu Asn Gly Glu Asp         #            30                                                               - Gln Asp Ile Leu Met Glu Asn Asn Leu Arg Ar - #g Pro Asn Leu Glu Ala         #        45                                                                   - Phe Asn Arg Ala Val Lys Ser Leu Gln Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                - Met Ala Asn Cys Ser Asn Met Ile Asp Glu Il - #e Ile Thr His Leu Lys         #                15                                                           - Gln Pro Pro Leu Pro Leu Leu Asp Phe Asn As - #n Leu Asn Gly Glu Asp         #            30                                                               - Gln Asp Ile Leu Met Glu Asn Asn Leu Arg Ar - #g Pro Asn Leu Glu Ala         #        45                                                                   - Phe Asn Arg Ala Val Lys Ser Leu Gln Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Gl - #u His Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Ala Ile Glu Ser         #    60                                                                       - Ile Leu Lys Asn Leu Leu Pro Cys Leu Pro Le - #u Ala Thr Ala Ala Pro         #80                                                                           - Thr Arg His Pro Ile His Ile Lys Asp Gly As - #p Trp Asn Glu Phe Arg         #                95                                                           - Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Gl - #u Asn Ala Gln Ala Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Th - #r Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys His Leu Glu Asn Al - #a Ser Ala Ile Glu Ser         #    60                                                                       - Ile Leu Lys Asn Leu Leu Pro Cys Leu Pro Le - #u Ala Thr Ala Ala Pro         #80                                                                           - Thr Arg His Pro Ile His Ile Lys Asp Gly As - #p Trp Asn Glu Phe Arg         #                95                                                           - Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Gl - #u Asn Ala Gln Ala Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Val Pro Pro Ala Pro Leu Leu Asp Ser Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Ala Ile Glu Ser         #    60                                                                       - Ile Leu Lys Asn Leu Leu Pro Cys Leu Pro Le - #u Ala Thr Ala Ala Pro         #80                                                                           - Thr Arg His Pro Ile His Ile Lys Asp Gly As - #p Trp Asn Glu Phe Arg         #                95                                                           - Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Gl - #u Asn Ala Gln Ala Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Th - #r Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys His Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Val Pro Pro Ala Pro Leu Leu Asp Ser Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Val Pro Pro Ala Pro Leu Leu Asp Ser Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Th - #r Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys His Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Gl - #u His Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Val Pro Pro Ala Pro Leu Leu Asp Ser Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Gl - #u His Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ser Glu Asp         #            30                                                               - Met Asp Ile Leu Met Glu Arg Asn Leu Arg Th - #r Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys His Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Val Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Thr Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Ser Leu Gl - #u His Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:40:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Asp Arg Asn Leu Arg Le - #u Ser Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:41:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Al - #a Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Ser Leu Asp Pro Asn As - #n Leu Asn Asp Glu Asp         #            30                                                               - Met Ser Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:42:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Asp Glu Asp         #            30                                                               - Met Ser Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:43:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Ala Glu Asp         #            30                                                               - Val Asp Ile Leu Met Asp Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:44:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Asp Glu Asp         #            30                                                               - Val Ser Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:45:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Il - #e Ile His His Leu Lys         #                15                                                           - Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn As - #n Leu Asn Asp Glu Asp         #            30                                                               - Met Ser Ile Leu Met Glu Arg Asn Leu Arg Le - #u Pro Asn Leu Glu Ser         #        45                                                                   - Phe Val Arg Ala Val Lys Asn Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:46:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 125 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                - Met Ala Tyr Pro Glu Thr Asp Tyr Lys Asp As - #p Asp Asp Lys Asn Cys         #                15                                                           - Ser Ile Met Ile Asp Glu Ile Ile His His Le - #u Lys Arg Pro Pro Ala         #            30                                                               - Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Gl - #u Asp Val Asp Ile Leu         #        45                                                                   - Met Glu Arg Asn Leu Arg Leu Pro Asn Leu Gl - #u Ser Phe Val Arg Ala         #    60                                                                       - Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Gl - #u Ala Ile Leu Arg Asn         #80                                                                           - Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Al - #a Pro Ser Arg His Pro         #                95                                                           - Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Ph - #e Arg Glu Lys Leu Thr         #           110                                                               - Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Gl - #u Gln Gln                     #       125                                                                   - (2) INFORMATION FOR SEQ ID NO:47:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 125 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                - Met Ala Tyr Pro Glu Thr Asp Tyr Lys Asp As - #p Asp Asp Lys Asn Cys         #                15                                                           - Ser Ile Met Ile Asp Glu Ile Ile His His Le - #u Lys Arg Pro Pro Asn         #            30                                                               - Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Gl - #u Asp Met Asp Ile Leu         #        45                                                                   - Met Glu Arg Asn Leu Arg Thr Pro Asn Leu Le - #u Ala Phe Val Arg Ala         #    60                                                                       - Val Lys His Leu Glu Asn Ala Ser Gly Ile Gl - #u Ala Ile Leu Arg Asn         #80                                                                           - Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Al - #a Pro Ser Arg His Pro         #                95                                                           - Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Ph - #e Arg Glu Lys Leu Thr         #           110                                                               - Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Gl - #u Gln Gln                     #       125                                                                   - (2) INFORMATION FOR SEQ ID NO:48:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 113 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                - Met Ala Asn Cys Ser Ile Met Ile Asp Glu Le - #u Ile His His Leu Lys         #                15                                                           - Ile Pro Pro Asn Pro Ser Leu Asp Ser Ala As - #n Leu Asn Ser Glu Asp         #            30                                                               - Val Ser Ile Leu Met Glu Arg Asn Leu Arg Th - #r Pro Asn Leu Leu Ala         #        45                                                                   - Phe Val Arg Ala Val Lys His Leu Glu Asn Al - #a Ser Gly Ile Glu Ala         #    60                                                                       - Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Se - #r Ala Thr Ala Ala Pro         #80                                                                           - Ser Arg His Pro Ile Ile Ile Lys Ala Gly As - #p Trp Gln Glu Phe Arg         #                95                                                           - Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Gl - #u Gln Ala Gln Glu Gln         #           110                                                               - Gln                                                                         - (2) INFORMATION FOR SEQ ID NO:49:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 134 amino                                                         (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                - Met Ala Pro Met Thr Gln Thr Thr Ser Leu Ly - #s Thr Ser Trp Val Asn         #                15                                                           - Cys Ser Asn Met Ile Asp Glu Ile Ile Thr Hi - #s Leu Lys Gln Pro Pro         #            30                                                               - Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gl - #y Glu Asp Gln Asp Ile         #        45                                                                   - Leu Met Glu Asn Asn Leu Arg Arg Pro Asn Le - #u Glu Ala Phe Asn Arg         #    60                                                                       - Ala Val Lys Ser Leu Gln Asn Ala Ser Ala Il - #e Glu Ser Ile Leu Lys         #80                                                                           - Asn Leu Leu Pro Cys Leu Pro Leu Ala Thr Al - #a Ala Pro Thr Arg His         #                95                                                           - Pro Ile His Ile Lys Asp Gly Asp Trp Asn Gl - #u Phe Arg Arg Lys Leu         #           110                                                               - Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala Gl - #n Ala Gln Gln Thr Thr         #       125                                                                   - Leu Ser Leu Ala Ile Phe                                                         130                                                                       - (2) INFORMATION FOR SEQ ID NO:50:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 36 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "synthetic DNA"RIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                #       36         GCCA GAATGGAGCT GACTGA                                     - (2) INFORMATION FOR SEQ ID NO:51:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 34 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "synthetic DNA"RIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                #        34        CCCT TCCTGAGACA GATT                                       - (2) INFORMATION FOR SEQ ID NO:52:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 45 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "synthetic DNA"RIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                #45                CNGC NCCNCCTGCT TGTGACCTCC GAGTC                           - (2) INFORMATION FOR SEQ ID NO:53:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 33 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "synthetic DNA"RIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                #         33       CGCA GAGGGTGGAC CCT                                        - (2) INFORMATION FOR SEQ ID NO:54:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 465 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                - ATGGCGTCTC CGGCGCCGCC TGCTTGTGAC CTCCGAGTCC TCAGTAAACT GC - #TTCGTGAC         60                                                                          - TCCCATGTCC TTCACAGCAG ACTGAGCCAG TGCCCAGAGG TTCACCCTTT GC - #CTACACCT        120                                                                          - GTCCTGCTGC CTGCTGTGGA CTTTAGCTTG GGAGAATGGA AAACCCAGAT GG - #AGGAGACC        180                                                                          - AAGGCACAGG ACATTCTGGG AGCAGTGACC CTTCTGCTGG AGGGAGTGAT GG - #CAGCACGG        240                                                                          - GGACAACTGG GACCCACTTG CCTCTCATCC CTCCTGGGGC AGCTTTCTGG AC - #AGGTCCGT        300                                                                          - CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAACCCAGC TTCCTCCACA GG - #GCAGGACC        360                                                                          - ACAGCTCACA AGGATCCCAA TGCCATCTTC CTGAGCTTCC AACACCTGCT CC - #GAGGAAAG        420                                                                          #                 465GT AGGAGGGTCC ACCCTCTGCG TCAGG                           - (2) INFORMATION FOR SEQ ID NO:55:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 353 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                - Met Glu Leu Thr Glu Leu Leu Leu Val Val Me - #t Leu Leu Leu Thr Ala         #                15                                                           - Arg Leu Thr Leu Ser Ser Pro Ala Pro Pro Al - #a Cys Asp Leu Arg Val         #            30                                                               - Leu Ser Lys Leu Leu Arg Asp Ser His Val Le - #u His Ser Arg Leu Ser         #        45                                                                   - Gln Cys Pro Glu Val His Pro Leu Pro Thr Pr - #o Val Leu Leu Pro Ala         #    60                                                                       - Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gl - #n Met Glu Glu Thr Lys         #80                                                                           - Ala Gln Asp Ile Leu Gly Ala Val Thr Leu Le - #u Leu Glu Gly Val Met         #                95                                                           - Ala Ala Arg Gly Gln Leu Gly Pro Thr Cys Le - #u Ser Ser Leu Leu Gly         #           110                                                               - Gln Leu Ser Gly Gln Val Arg Leu Leu Leu Gl - #y Ala Leu Gln Ser Leu         #       125                                                                   - Leu Gly Thr Gln Leu Pro Pro Gln Gly Arg Th - #r Thr Ala His Lys Asp         #   140                                                                       - Pro Asn Ala Ile Phe Leu Ser Phe Gln His Le - #u Leu Arg Gly Lys Val         145                 1 - #50                 1 - #55                 1 -       #60                                                                           - Arg Phe Leu Met Leu Val Gly Gly Ser Thr Le - #u Cys Val Arg Arg Ala         #               175                                                           - Pro Pro Thr Thr Ala Val Pro Ser Arg Thr Se - #r Leu Val Leu Thr Leu         #           190                                                               - Asn Glu Leu Pro Asn Arg Thr Ser Gly Leu Le - #u Glu Thr Asn Phe Thr         #       205                                                                   - Ala Ser Ala Arg Thr Thr Gly Ser Gly Leu Le - #u Lys Trp Gln Gln Gly         #   220                                                                       - Phe Arg Ala Lys Ile Pro Gly Leu Leu Asn Gl - #n Thr Ser Arg Ser Leu         225                 2 - #30                 2 - #35                 2 -       #40                                                                           - Asp Gln Ile Pro Gly Tyr Leu Asn Arg Ile Hi - #s Glu Leu Leu Asn Gly         #               255                                                           - Thr Arg Gly Leu Phe Pro Gly Pro Ser Arg Ar - #g Thr Leu Gly Ala Pro         #           270                                                               - Asp Ile Ser Ser Gly Thr Ser Asp Thr Gly Se - #r Leu Pro Pro Asn Leu         #       285                                                                   - Gln Pro Gly Tyr Ser Pro Ser Pro Thr His Pr - #o Pro Thr Gly Gln Tyr         #   300                                                                       - Thr Leu Phe Pro Leu Pro Pro Thr Leu Pro Th - #r Pro Val Val Gln Leu         305                 3 - #10                 3 - #15                 3 -       #20                                                                           - His Pro Leu Leu Pro Asp Pro Ser Ala Pro Th - #r Pro Thr Pro Thr Ser         #               335                                                           - Pro Leu Leu Asn Thr Ser Tyr Thr His Ser Gl - #n Asn Leu Ser Gln Glu         #           350                                                               - Gly                                                                         - (2) INFORMATION FOR SEQ ID NO:56:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 174 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                - Met Glu Leu Thr Glu Leu Leu Leu Val Val Me - #t Leu Leu Leu Thr Ala         #                15                                                           - Arg Leu Thr Leu Ser Ser Pro Ala Pro Pro Al - #a Cys Asp Leu Arg Val         #            30                                                               - Leu Ser Lys Leu Leu Arg Asp Ser His Val Le - #u His Ser Arg Leu Ser         #        45                                                                   - Gln Cys Pro Glu Val His Pro Leu Pro Thr Pr - #o Val Leu Leu Pro Ala         #    60                                                                       - Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gl - #n Met Glu Glu Thr Lys         #80                                                                           - Ala Gln Asp Ile Leu Gly Ala Val Thr Leu Le - #u Leu Glu Gly Val Met         #                95                                                           - Ala Ala Arg Gly Gln Leu Gly Pro Thr Cys Le - #u Ser Ser Leu Leu Gly         #           110                                                               - Gln Leu Ser Gly Gln Val Arg Leu Leu Leu Gl - #y Ala Leu Gln Ser Leu         #       125                                                                   - Leu Gly Thr Gln Leu Pro Pro Gln Gly Arg Th - #r Thr Ala His Lys Asp         #   140                                                                       - Pro Asn Ala Ile Phe Leu Ser Phe Gln His Le - #u Leu Arg Gly Lys Val         145                 1 - #50                 1 - #55                 1 -       #60                                                                           - Arg Phe Leu Met Leu Val Gly Gly Ser Thr Le - #u Cys Val Arg                 #               170                                                           - (2) INFORMATION FOR SEQ ID NO:57:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1059 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                - ATGGAGCTGA CTGAATTGCT CCTCGTGGTC ATGCTTCTCC TAACTGCAAG GC - #TAACGCTG         60                                                                          - TCCAGCCCGG CTCCTCCTGC TTGTGACCTC CGAGTCCTCA GTAAACTGCT TC - #GTGACTCC        120                                                                          - CATGTCCTTC ACAGCAGACT GAGCCAGTGC CCAGAGGTTC ACCCTTTGCC TA - #CACCTGTC        180                                                                          - CTGCTGCCTG CTGTGGACTT TAGCTTGGGA GAATGGAAAA CCCAGATGGA GG - #AGACCAAG        240                                                                          - GCACAGGACA TTCTGGGAGC AGTGACCCTT CTGCTGGAGG GAGTGATGGC AG - #CACGGGGA        300                                                                          - CAACTGGGAC CCACTTGCCT CTCATCCCTC CTGGGGCAGC TTTCTGGACA GG - #TCCGTCTC        360                                                                          - CTCCTTGGGG CCCTGCAGAG CCTCCTTGGA ACCCAGCTTC CTCCACAGGG CA - #GGACCACA        420                                                                          - GCTCACAAGG ATCCCAATGC CATCTTCCTG AGCTTCCAAC ACCTGCTCCG AG - #GAAAGGTG        480                                                                          - CGTTTCCTGA TGCTTGTAGG AGGGTCCACC CTCTGCGTCA GGCGGGCCCC AC - #CCACCACA        540                                                                          - GCTGTCCCCA GCAGAACCTC TCTAGTCCTC ACACTGAACG AGCTCCCAAA CA - #GGACTTCT        600                                                                          - GGATTGTTGG AGACAAACTT CACTGCCTCA GCCAGAACTA CTGGCTCTGG GC - #TTCTGAAG        660                                                                          - TGGCAGCAGG GATTCAGAGC CAAGATTCCT GGTCTGCTGA ACCAAACCTC CA - #GGTCCCTG        720                                                                          - GACCAAATCC CCGGATACCT GAACAGGATA CACGAACTCT TGAATGGAAC TC - #GTGGACTC        780                                                                          - TTTCCTGGAC CCTCACGCAG GACCCTAGGA GCCCCGGACA TTTCCTCAGG AA - #CATCAGAC        840                                                                          - ACAGGCTCCC TGCCACCCAA CCTCCAGCCT GGATATTCTC CTTCCCCAAC CC - #ATCCTCCT        900                                                                          - ACTGGACAGT ATACGCTCTT CCCTCTTCCA CCCACCTTGC CCACCCCTGT GG - #TCCAGCTC        960                                                                          - CACCCCCTGC TTCCTGACCC TTCTGCTCCA ACGCCCACCC CTACCAGCCC TC - #TTCTAAAC       1020                                                                          #  1059            CCCA GAATCTGTCT CAGGAAGGG                                  - (2) INFORMATION FOR SEQ ID NO:58:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 408 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                #acid (ii) MOLECULE TYPE: DNA other nucleic                                   #= "synthetic DNA"RIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                - ATGGCTCCAA TGACTCAGAC TACTTCTCTT AAGACTTCTT GGGTTAACTG CT - #CTAACATG         60                                                                          - ATCGATGAAA TTATAACACA CTTAAAGCAG CCACCTTTGC CTTTGCTGGA CT - #TCAACAAC        120                                                                          - CTCAATGGGG AAGACCAAGA CATTCTGATG GAAAATAACC TTCGAAGGCC AA - #ACCTGGAG        180                                                                          - GCATTCAACA GGGCTGTCAA GAGTTTACAG AATGCATCAG CAATTGAGAG CA - #TTCTTAAA        240                                                                          - AATCTCCTGC CATGTCTGCC CCTGGCCACG GCCGCACCCA CGCGACATCC AA - #TCCATATC        300                                                                          - AAGGACGGTG ACTGGAATGA ATTCCGTCGT AAACTGACCT TCTATCTGAA AA - #CCTTGGAG        360                                                                          #               408AGAC CACTCTGTCG CTAGCGATCT TTTAATAA                        __________________________________________________________________________

What is claimed is:
 1. A method of treating a patient having ahematopoietic disorder comprising; administering to said patient atherapeutically effective amount of a composition comprising;a modifiedhuman interleukin-3 (hIL-3) amino acid sequence, wherein said modifiedsequence differs from the sequence of native (1-133) hIL-3 by thereplacement of from 4 to about 44 of the residues corresponding topositions 17-123 of native (1-133) hIL-3 by other amino acids, with theproviso that the residues corresponding to positions 101 and 116 are notAla or Val, respectively; wherein said modified sequence optionallyfurther differs from the sequence of native (1-133) hIL-3 by thedeletion of from 1 to 14 residues from the N-terminus of native (1-133)hIL-3, the deletion of from 1 to 15 residues from the C-terminus ofnative (1-133) hIL-3, or both; and wherein said modified interleukin-3(hIL-3) amino acid sequence has at least three times greater activity,relative to native human interleukin-3, in at least one assay selectedfrom the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine alymphokine, an interleukin and a hematopoietic growth factor.
 2. Amethod of treating a patient having a hematopoietic disorder comprising;administering to said patient a therapeutically effective amount of acomposition comprising;a human interleukin-3 variant polypeptideselected from the group consisting of:(a) a sequence of SEQ ID NO:1; and(b) a polypeptide comprising an N-terminal methionine residue, alanineresidue or methionine-alanine di-peptide immediately preceding saidsequence according to (a); wherein;Xaa at position 17 is Ser, Lys, Gly,Asp, Met, Gln, or Arg; Xaa at position 18 is Asn, His, Leu, Ile, Phe,Arg, or Gln; Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala; Xaa atposition 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser orVal; Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,Leu, Val or Gly; Xaa at position 23 is Ile, Val, Ala, Leu, Gly, Trp,Lys, Phe, Ser, or Arg; Xaa at position 24 is Ile, Gly, Val, Arg, Ser,Phe, or Leu; Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp; Xaa atposition 27 is Leu, Gly, Arg, Thr, Ser, or Ala; Xaa at position 28 isLys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaa at position 29 is Gln,Asn, Leu, Pro, Arg, or Val; Xaa at position 30 is Pro, His, Thr, Gly,Asp, Gln, Ser, Leu, or Lys; Xaa at position 31 is Pro, Asp, Gly, Ala,Arg, Leu, or Gln; Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly,Ala, or Glu; Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu; Xaaat position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr, Arg, Ala, Phe,Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser,Pro, Trp, or Ile; Xaa at position 38 is Asn, or Ala; Xaa at position 40is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met,or Pro; Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn,Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr, Gly or Ser; Xaa at position44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln, Ala or Pro;Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp,Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe,Ser, Thr, Cys, Glu, Asn, Gln, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaaat position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; Xaa at position48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met, Val orAsn; Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile,Val, His, Phe, Met or Gln; Xaa at position 51 is Asn, Arg, Met, Pro,Ser, Thr, or His; Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, orThr; Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, orMet; Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys,His, Ala or Leu; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His, Thr, Ala,Tyr, Phe, Leu, Val or Lys; Xaa at position 57 is Asn or Gly; Xaa atposition 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys; Xaa at position 59is Glu, Tyr, His, Leu, Pro, or Arg; Xaa at position 60 is Ala, Ser, Pro,Tyr, Asn, or Thr; Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, orSer; Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val; Xaa atposition 64 is Ala, Asn, Pro, Ser, or Lys; Xaa at position 65 is Val,Thr, Pro, His, Leu, Phe, or Ser; Xaa at position 66 is Lys, Ile, Arg,Val, Asn, Glu, or Ser; Xaa at position 67 is Ser, Ala, Phe, Val, Gly,Asn, Ile, Pro, or His; Xaa at position 68 is Leu, Val, Trp, Ser, Ile,Phe, Thr, or His; Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg,Trp, Gly, or Leu; Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, orAsn; Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa atposition 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala; Xaa at position 75 isGlu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gln, or Leu; Xaa at position 76is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp; Xaa at position 77 isIle, Ser, Arg, Thr, or Leu; Xaa at position 78 is Leu, Ala, Ser, Glu,Phe, Gly, or Arg; Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile,Gly, or Asp; Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, orArg; Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr,Ser, Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 83 is Pro, Ala,Thr, Trp, Arg, or Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, orVal; Xaa at position 85 is Leu, Asn, Val, or Gln; Xaa at position 86 isPro, Cys, Arg, Ala, or Lys; Xaa at position 87 is Leu, Ser, Trp, or Gly;Xaa at position 88 is Ala, Lys, Arg, Val, or Trp; Xaa at position 89 isThr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 90 isAla, Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 91 is Ala,Pro, Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe,Arg, Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr,Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile,Ser, Glu, Leu, Val, Gln, Lys, His, Ala, or Pro; Xaa at position 95 isHis, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe,Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaaat position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, or Pro; Xaa at position 101 is Asp; Xaa at position 102is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 103 is Asp, orSer; Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln,Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Phe, Ser,Trp, Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu,Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys,Asp, Leu, Thr, Ile, Gln, His, Ser, Ala or Pro; Xaa at position 109 isArg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys,Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser, Ala, or Trp; Xaa atposition 111 is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr,Val, Gln, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser,Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu,Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 isLys; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa atposition 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa atposition 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa atposition 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 isGln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa atposition 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;wherein from 4to about 44 of the amino acids designated by Xaa are different from thecorresponding amino acids of native (1-133) human interleukin-3; whereinfrom 1 to 14 amino acids are optionally deleted from the N-terminusand/or from 1 to 15 amino acids are optionally deleted from theC-terminus of said sequence of SEQ ID NO:1; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor.
 3. Themethod of claim 2, wherein in said human interleukin-3 mutantpolypeptide, the amino acids which differ from the corresponding residuein native human interleukin-3 are selected from the group consistingof:position 17 wherein Xaa is Ser, Gly, Asp, or Gln; position 18 whereinXaa is Asn, His, or Ile; position 23 wherein Xaa is Ile, Ala, Leu, orGly; position 25 wherein Xaa is Thr, His, or Gln; position 26 whereinXaa is His or Ala; position 29 wherein Xaa is Gln or Asn; position 30wherein Xaa is Pro or Gly; position 32 wherein Xaa is Leu, Arg, Asn, orAla; position 34 wherein Xaa is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile,Phe, Thr, or Met; position 35 wherein Xaa is Leu, Ala, Asn, or Pro;position 38 wherein Xaa is Asn or Ala; position 42 wherein Xaa is Gly,Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr or Arg; position 45 wherein Xaais Gln, Val, Met, Leu, Ala, Asn, Glu, or Lys; position 46 wherein Xaa isAsp, Phe, Ser, Gln, Glu, His, Val or Thr; position 50 wherein Xaa isGlu, Asn, Ser or Asp; position 51 wherein Xaa is Asn, Arg, Pro, Thr, orHis; position 55 wherein Xaa is Arg, Leu, or Gly; position 56 whereinXaa is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln; position 62 wherein Xaais Asn, Pro, or Thr; position 64 wherein Xaa is Ala or Asn; position 65wherein Xaa is Val or Thr; position 67 wherein Xaa is Ser or Phe;position 68 wherein Xaa is Leu or Phe; position 69 wherein Xaa is Gln,Ala, Glu, or Arg; position 76 wherein Xaa is Ser, Val, Asn, Pro, or Gly;position 77 wherein Xaa is Ile or Leu; position 79 wherein Xaa is Lys,Asn, Met, Arg, Ile, or Gly; position 80 wherein Xaa is Asn, Gly, Glu, orArg; position 82 wherein Xaa is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His,Met, Phe, Ser, Thr, Tyr or Val; position 87 wherein Xaa is Leu or Ser;position 88 wherein Xaa is Ala or Trp; position 91 wherein Xaa is Ala orPro; position 93 wherein Xaa is Thr, Asp, or Ala; position 95 whereinXaa is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; position 98 wherein Xaais His, Ile, Asn, Ala, Thr, Gln, Glu, Lys, Met, Ser, Tyr, Val or Leu;position 99 wherein Xaa is Ile or Leu; position 100 wherein Xaa is Lysor Arg; position 101 wherein Xaa is Asp; position 105 wherein Xaa isAsn, Pro, Ser, Ile or Asp; position 108 wherein Xaa is Arg, Ala, or Ser;position 109 wherein Xaa is Arg, Thr, Glu, Leu, or Ser; position 112wherein Xaa is Thr or Gln; position 116 wherein Xaa is Lys; position 120wherein Xaa is Asn, Pro, Leu, His, Val, or Gln; position 121 wherein Xaais Ala, Ser, Ile, Pro, or Asp; position 122 wherein Xaa is Gln, Met,Trp, Phe, Pro, His, Ile, or Tyr; position 123 wherein Xaa is Ala, Met,Glu, Ser, or Leu.
 4. The method of claim 2, wherein in said humaninterleukin-3 mutant polypeptide, the amino acids which differ from thecorresponding residue in native human interleukin-3 are selected fromthe group consisting of:position 42 wherein Xaa is Gly, Asp, Ser, Ile,Leu, Met, Tyr, or Ala; position 45 wherein Xaa is Gln, Val, Met or Asn;position 46 wherein Xaa is Asp, Ser, Gln, His or Val; position 50wherein Xaa is Glu or Asp; position 51 wherein Xaa is Asn, Pro or Thr;position 62 wherein Xaa is Asn or Pro; position 76 wherein Xaa is Ser,or Pro; position 82 wherein Xaa is Leu, Trp, Asp, Asn Glu, His, Phe, Seror Tyr; position 95 wherein Xaa is His, Arg, Thr, Asn or Ser; position98 wherein Xaa is His, Ile, Leu, Ala, Gln, Lys, Met, Ser, Tyr or Val;position 100 wherein Xaa is Lys or Arg; position 105 wherein Xaa is Asn,or Pro; position 108 wherein Xaa is Arg, Ala, or Ser; position 121wherein Xaa is Ala, or Ile; position 122 wherein Xaa is Gln, or Ile; andposition 123 wherein Xaa is Ala, Met or Glu.
 5. A method of treating apatient having a hematopoietic disorder comprising; administering tosaid patient a therapeutically effective amount of a compositioncomprising;a human interleukin-3 variant polypeptide selected from thegroup consisting of:(a) a sequence of SEQ ID NO:4; and (b) a polypeptidecomprising an N-terminal residue, alanine residue or methionine-alaninedi-peptide immediately preceding said sequence according to (a);wherein;Xaa at position 3 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaaat position 4 is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 5is Met, Phe, Ile, Arg, Gly, Ala, or Cys; Xaa at position 6 is Ile, Cys,Gln, Glu, Arg, Pro, or Ala; Xaa at position 7 is Asp, Phe, Lys, Arg,Ala, Gly, Glu, Gln, Asn, Thr, Ser or Val; Xaa at position 8 is Glu, Trp,Pro, Ser, Ala, His, Asp, Asn, Gln, Leu, Val, or Gly; Xaa at position 9is Ile, Val, Ala, Leu, Gly, Trp, Lys, Phe, Ser, or Arg; Xaa at position10 is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 11 is Thr,His, Gly, Gln, Arg, Pro, or Ala; Xaa at position 12 is His, Thr, Phe,Gly, Arg, Ala, or Trp; Xaa at position 13 is Leu, Gly, Arg, Thr, Ser, orAla; Xaa at position 14 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaaat position 15 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 16 isPro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys; Xaa at position 17 isPro, Asp, Gly, Ala, Arg, Leu, or Gln; Xaa at position 18 is Leu, Val,Arg, Gln, Asn, Gly, Ala, or Glu; Xaa at position 19 is Pro, Leu, Gln,Ala, Thr, or Glu; Xaa at position 20 is Leu, Val, Gly, Ser, Lys, Glu,Gln, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 21 is Leu, Ala,Gly, Asn, Pro, Gln, or Val; Xaa at position 22 is Asp, Leu, or Val; Xaaat position 23 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 24 is Asn,or Ala; Xaa at position 26 is Leu, Trp, or Arg; Xaa at position 27 isAsn, Cys, Arg, Leu, His, Met, Pro; Xaa at position 28 is Gly, Asp, Ser,Cys, Ala, Lys, Asn, Thr, Leu, Val, Glu, Phe, Tyr, Ile or Met; Xaa atposition 29 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr,Gly or Ser; Xaa at position 30 is Asp, Ser, Leu, Arg, Lys, Thr, Met,Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 31 is Gln, Pro, Phe,Val, Met, Leu, Thr, Lys, Asp, Asn, Arg, Ser, Ala, Ile, Glu, His or Trp;Xaa at position 32 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly; Xaa at position 33 is Ile, Gly, Val, Ser,Arg, Pro, or His; Xaa at position 34 is Leu, Ser, Cys, Arg, Ile, His,Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 35 is Met,Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 36 is Glu, Leu,Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gln; Xaaat position 37 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position38 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 39 is Leu,Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 40 is Arg,Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His, Ala or Leu; Xaa at position41 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 42 is Pro, Gly,Cys, Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaaat position 43 is Asn or Gly; Xaa at position 44 is Leu, Ser, Asp, Arg,Gln, Val, or Cys; Xaa at position 45 is Glu, Tyr, His, Leu, Pro, or Arg;Xaa at position 46 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position47 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 48 is Asn,His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 49 is Arg, Tyr,Trp, Lys, Ser, His, Pro, or Val; Xaa at position 50 is Ala, Asn, Pro,Ser, or Lys; Xaa at position 51 is Val, Thr, Pro, His, Leu, Phe, or Ser;Xaa at position 52 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa atposition 53 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa atposition 54 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa atposition 55 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa atposition 56 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 57 isAla, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 58is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 59 is Ala,Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 60 is Ile, Met,Thr, Pro, Arg, Gly, Ala; Xaa at position 61 is Glu, Lys, Gly, Asp, Pro,Trp, Arg, Ser, Gln, or Leu; Xaa at position 62 is Ser, Val, Ala, Asn,Trp, Glu, Pro, Gly, or Asp; Xaa at position 63 is Ile, Ser, Arg, Thr, orLeu; Xaa at position 64 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa atposition 65 is Lys, Thr, Gly, Asn, Met, Arg, Ile, or Asp; Xaa atposition 66 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa atposition 67 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa atposition 68 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser,Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 69 is Pro, Ala, Thr,Trp, Arg, or Met; Xaa at position 70 is Cys, Glu, Gly, Arg, Met, or Val;Xaa at position 71 is Leu, Asn, Val, or Gln; Xaa at position 72 is Pro,Cys, Arg, Ala, or Lys; Xaa at position 73 is Leu, Ser, Trp, or Gly; Xaaat position 74 is Ala, Lys, Arg, Val, or Trp; Xaa at position 75 is Thr,Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 76 is Ala,Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 77 is Ala, Pro,Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 78 is Pro, Phe, Arg,Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 79 is Thr, Asp,Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 80 is Arg, Ile, Ser,Glu, Leu, Val, Gln, Lys, His, Ala or Pro; Xaa at position 81 is His,Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile orTyr; Xaa at position 82 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa atposition 83 is Ile, Val, Lys, Ala, or Asn; Xaa at position 84 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 85 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 86 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, Pro; Xaa at position 87 is Asp; Xaa at position 88 isGly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 89 is Asp, or Ser;Xaa at position 90 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly; Xaa at position 91 is Asn, Pro, Ala, Phe, Ser, Trp,Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 92 is Glu, Ser,Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 94 is Arg, Lys, Asp,Leu, Thr, Ile, Gln, His, Ser, Ala, or Pro; Xaa at position 95 is Arg,Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 96 is Lys, Asn,Thr, Leu, Gln, Arg, His, Glu, Ser, Ala or Trp; Xaa at position 97 isLeu, Ile, Arg, Asp, or Met; Xaa at position 98 is Thr, Val, Gln, Tyr,Glu, His, Ser, or Phe; Xaa at position 99 is Phe, Ser, Cys, His, Gly,Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 100 is Tyr,Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 101 is Leu, Asn, Val,Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 102 is Lys; Xaa atposition 103 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position104 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 105 isGlu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 106 is Asn,Ala, Pro, Leu, His, Val, or Gln; Xaa at position 107 is Ala, Ser, Ile,Asn, Pro, Lys, Asp, or Gly; Xaa at position 108 is Gln, Ser, Met, Trp,Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 109 is Ala, Met,Glu, His, Ser, Pro, Tyr, or Leu;wherein from 4 to about 44 of the aminoacids designated by Xaa are different from the corresponding nativeamino acids of (1-133) human interleukin-3; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor.
 6. Themethod of claim 5, wherein in said human interleukin-3 mutantpolypeptide, the amino acids which differ from the corresponding residuein native human interleukin-3 are selected from the group consistingof:position 3 wherein Xaa is Ser, Gly, Asp, or Gln; position 4 whereinXaa is Asn, His, or Ile; position 9 wherein Xaa is Ile, Ala, Leu, orGly; position 11 wherein Xaa is Thr, His, or Gln; position 12 whereinXaa is His or Ala; position 15 wherein Xaa is Gln or Asn; position 16wherein Xaa is Pro or Gly; position 18 wherein Xaa is Leu, Arg, Asn, orAla; position 20 wherein Xaa is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile,Phe, Thr or Met; position 21 wherein Xaa is Leu, Ala, Asn, or Pro;position 24 wherein Xaa is Asn or Ala; position 28 wherein Xaa is Gly,Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr or Arg; position 31 wherein Xaais Gln, Val, Met, Leu, Ala, Asn, Glu or Lys; position 32 wherein Xaa isAsp, Phe, Ser, Ala, Gln, Glu, His, Val or Thr; position 36 wherein Xaais Glu, Asn, Ser or Asp; position 37 wherein Xaa is Asn, Arg, Pro, Thr,or His; position 41 wherein Xaa is Arg, Leu, or Gly; position 42 whereinXaa is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln; position 48 wherein Xaais Asn, Pro, or Thr; position 50 wherein Xaa is Ala or Asn; position 51wherein Xaa is Val or Thr; position 53 wherein Xaa is Ser or Phe;position 54 wherein Xaa is Leu or Phe; position 55 wherein Xaa is Gln,Ala, Glu, or Arg; position 62 wherein Xaa is Ser, Val, Asn, Pro, or Gly;position 63 wherein Xaa is Ile or Leu; position 65 wherein Xaa is Lys,Asn, Met, Arg, Ile, or Gly; position 66 wherein Xaa is Asn, Gly, Glu, orArg; position 68 wherein Xaa is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His,Met, Phe, Ser, Thr, Tyr or Val; position 73 wherein Xaa is Leu or Ser;position 74 wherein Xaa is Ala or Trp; position 77 wherein Xaa is Ala orPro; position 79 wherein Xaa is Thr, Asp, or Ala; position 81 whereinXaa is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; position 84 wherein Xaais His, Ile, Asn, Ala, Thr, Arg, Gln, Glu, Lys, Met, Ser, Tyr, Val orLeu; position 85 wherein Xaa is Ile or Leu; position 86 wherein Xaa isLys or Arg; position 87 wherein Xaa is Asp; position 91 wherein Xaa isAsn, Pro, Ser, Ile or Asp; position 94 wherein Xaa is Arg, Ala, or Ser;position 95 wherein Xaa is Arg, Thr, Glu, Leu, or Ser; position 98wherein Xaa is Thr or Gln; position 102 wherein Xaa is Lys; position 103wherein Xaa is Thr, Ala, His, Phe, Tyr or Ser; position 106 wherein Xaais Asn, Pro, Leu, His, Val, or Gln; position 107 wherein Xaa is Ala,Ser, Ile, Pro, or Asp; position 108 wherein Xaa is Gln, Met, Trp, Phe,Pro, His, Ile, or Tyr; and position 109 wherein Xaa is Ala, Met, Glu,Ser, or Leu.
 7. The method of claim 6, wherein the sequence of saidhuman interleukin-3 variant polypeptide is selected from the groupconsisting of:SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ IDNO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ IDNO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ IDNO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ IDNO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ IDNO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ IDNO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ IDNO:48, and SEQ ID NO:49.
 8. A method of treating a patient having ahematopoietic disorder comprising; administering to said patient atherapeutically effective amount of a composition comprising;a humaninterleukin-3 variant polypeptide selected from the group consistingof:(a) a sequence of SEQ ID NO:8; and (b) a polypeptide comprising anN-terminal residue, alanine residue or methionine-alanine di-peptideimmediately preceding said sequence according to (a); wherein;Xaa atposition 4 is Asn or Ile; Xaa at position 5 is Met, Ala or Ile; Xaa atposition 6 is Ile, Pro or Leu; Xaa at position 9 is Ile, Ala or Leu; Xaaat position 11 is Thr or His; Xaa at position 15 is Gln, Arg, Val orLeu; Xaa at position 18 is Leu, Ala, Asn or Arg; Xaa at position 20 isLeu or Ser; Xaa at position 23 is Phe, Pro, or Ser; Xaa at position 24is Asn or Ala; Xaa at position 28 is Gly, Ala, Ser, Asp or Asn; Xaa atposition 31 is Gln, Val, or Met; Xaa at position 32 is Asp or Ser; Xaaat position 35 is Met, Ile, Leu or Asp; Xaa at position 36 is Glu orAsp; Xaa at position 37 is Asn, Arg or Ser; Xaa at position 41 is Arg,Leu, or Thr; Xaa at position 42 is Pro or Ser; Xaa at position 45 is Gluor Leu; Xaa at position 46 is Ala or Ser; Xaa at position 48 is Asn, Valor Pro; Xaa at position 49 is Arg or His; Xaa at position 51 is Val orSer; Xaa at position 53 is Ser, Asn, His or Gly; Xaa at position 55 isGln or Glu; Xaa at position 59 is Ala or Gly; Xaa at position 62 is Ser,Ala or Pro; Xaa at position 65 is Lys, Arg or Ser; Xaa at position 67 isLeu, Glu, or Val; Xaa at position 68 is Leu, Glu, Val or Trp; Xaa atposition 71 is Leu or Val; Xaa at position 73 is Leu, Ser or Trp; Xaa atposition 74 is Ala or Trp; Xaa at position 77 is Ala or Pro; Xaa atposition 79 is Pro or Ser; Xaa at position 81 is His or Thr; Xaa atposition 84 is His, Ile, or Thr; Xaa at position 86 is Lys or Arg; Xaaat position 87 is Asp; Xaa at position 91 is Asn or Gln; Xaa at position95 is Arg, Glu, Leu; Xaa at position 98 is Thr or Gln; Xaa at position102 is Lys; Xaa at position 103 is Thr or Ser; Xaa at position 106 isAsn, Gln, or His; Xaa at position 109 is Ala or Glu;wherein from 4 toabout 44 of the amino acids designated by Xaa are different from thecorresponding amino acids of native (1-133) human interleukin-3; andwherein said human interleukin-3 variant polypeptide has at least threetimes greater activity, relative to native human interleukin-3, in atleast one assay selected from the group consisting of: AML cellproliferation, TF-1 cell proliferation and Methylcellulose assay; and afactor selected from the group consisting of: a colony stimulatingfactor, a cytokine, a lymphokine, an interleukin, and a hematopoieticgrowth factor.
 9. The method of claim 1, 2, 3, 4, 5, 6, 7 or 8 whereinsaid factor is selected from the group consisting of; GM-CSF, CSF-1,G-CSF, G-CSF (Ser¹⁷), M-CSF, erythropoietin (EPO), c-mpl ligand, IL-1,IL-4, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13,LIF, flt3 ligand, human growth hormone, B-cell growth factor, B-celldifferentiation factor, eosinophil differentiation factor and stem cellfactor (SCF).
 10. The method according to claim 9 wherein said ahematopoietic disorder is the result of a viral infection, bacterialinfection or fungal infection.
 11. The method according to claim 9wherein said a hematopoietic disorder is the result of cancer radiationtherapy or chemotherapy or a bone marrow suppressive drug.
 12. Themethod according to claim 1, 2, 3, 4, 5, 6, 7 or or 8 wherein said ahematopoietic disorder is the result of a viral infection, bacterialinfection or fungal infection.
 13. The method according to 1, 2, 3, 4,5, 6, 7 or 8 wherein said a hematopoietic disorder is the result ofcancer radiation therapy or chemotherapy or a bone marrow suppressivedrug.
 14. A method of treating a patient comprising the steps of;(i)administering to said patient an amount, effective to promote theproliferation and/or differentiation of hematopoietic cells in saidpatient, of a composition comprising;a modified human interleukin-3(hIL-3) amino acid sequence, wherein said modified sequence differs fromthe sequence of native (1-133) hIL-3 by the replacement of from 4 toabout 44 of the residues corresponding to positions 17-123 of native(1-133) hIL-3 by other amino acids, with the proviso that the residuescorresponding to positions 101 and 116 are not Ala or Val, respectively;wherein said modified sequence optionally further differs from thesequence of native (1-133) hIL-3 by the deletion of from 1 to 14residues from the N-terminus of native (1-133) hIL-3, the deletion offrom 1 to 15 residues from the C-terminus of native (1-133) hIL-3, orboth; and wherein said modified interleukin-3 (hIL-3) amino acidsequence has at least three times greater activity, relative to nativehuman interleukin-3, in at least one assay selected from the groupconsisting of: AML cell proliferation, TF-1 cell proliferation andMethylcellulose assay; and a factor selected from the group consistingof: a colony stimulating factor, a cytokine a lymphokine, an interleukinand a hematopoietic growth factor; (ii) removing hematopoietic cellsfrom said patient; (iii) administering cancer radiation therapy orchemotherapy to said patient; and (iv) returning said hematopoieticcells to said patient.
 15. A method of treating a patient comprising thesteps of:(i) administering to said patient an amount, effective topromote the proliferation and/or differentiation of hematopoietic cellsin said patient, of a composition comprising;a human interleukin-3variant polypeptide selected from the group consisting of:(a) a sequenceof SEQ ID NO:1; and (b) a polypeptide comprising an N-terminalmethionine residue, alanine residue or methionine-alanine di-peptideimmediately preceding said sequence according to (a); wherein;Xaa atposition 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaa at position 18is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 19 is Met, Phe,Ile, Arg, Gly, Ala, or Cys; Xaa at position 20 is Ile, Cys, Gln, Glu,Arg, Pro, or Ala; Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly,Glu, Gln, Asn, Thr, Ser or Val; Xaa at position 22 is Glu, Trp, Pro,Ser, Ala, His, Asp, Asn, Gln, Leu, Val or Gly; Xaa at position 23 isIle, Val, Ala, Leu, Gly, Trp, Lys, Phe, Ser, or Arg; Xaa at position 24is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 25 is Thr, His,Gly, Gln, Arg, Pro, or Ala; Xaa at position 26 is His, Thr, Phe, Gly,Arg, Ala, or Trp; Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaa atposition 29 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 30 isPro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys; Xaa at position 31 isPro, Asp, Gly, Ala, Arg, Leu, or Gln; Xaa at position 32 is Leu, Val,Arg, Gln, Asn, Gly, Ala, or Glu; Xaa at position 33 is Pro, Leu, Gln,Ala, Thr, or Glu; Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu,Gln, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala,Gly, Asn, Pro, Gln, or Val; Xaa at position 36 is Asp, Leu, or Val; Xaaat position 37 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 38 is Asn,or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 isAsn, Cys, Arg, Leu, His, Met, or Pro; Xaa at position 42 is Gly, Asp,Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaaat position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr,Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met,Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 45 is Gln, Pro, Phe,Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser,Arg, Pro, or His; Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His,Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met,Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 50 is Glu, Leu,Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gln; Xaaat position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 53 is Leu,Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 54 is Arg,Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His, Ala or Leu; Xaa at position55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 56 is Pro, Gly,Cys, Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaaat position 57 is Asn or Gly; Xaa at position 58 is Leu, Ser, Asp, Arg,Gln, Val, or Cys; Xaa at position 59 is Glu, Tyr, His, Leu, Pro, or Arg;Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 62 is Asn,His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 63 is Arg, Tyr,Trp, Lys, Ser, His, Pro, or Val; Xaa at position 64 is Ala, Asn, Pro,Ser, or Lys; Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa atposition 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa atposition 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa atposition 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa atposition 70 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 71 isAla, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 72is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 73 is Ala,Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 74 is Ile, Met,Thr, Pro, Arg, Gly, Ala; Xaa at position 75 is Glu, Lys, Gly, Asp, Pro,Trp, Arg, Ser, Gln, or Leu; Xaa at position 76 is Ser, Val, Ala, Asn,Trp, Glu, Pro, Gly, or Asp; Xaa at position 77 is Ile, Ser, Arg, Thr, orLeu; Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa atposition 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp; Xaa atposition 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa atposition 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa atposition 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser,Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 83 is Pro, Ala, Thr,Trp, Arg, or Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;Xaa at position 85 is Leu, Asn, Val, or Gln; Xaa at position 86 is Pro,Cys, Arg, Ala, or Lys; Xaa at position 87 is Leu, Ser, Trp, or Gly; Xaaat position 88 is Ala, Lys, Arg, Val, or Trp; Xaa at position 89 is Thr,Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 90 is Ala,Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 91 is Ala, Pro,Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe, Arg,Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr, Asp,Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser,Glu, Leu, Val, Gln, Lys, His, Ala, or Pro; Xaa at position 95 is His,Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, orTyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa atposition 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, or Pro; Xaa at position 101 is Asp; Xaa at position 102is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 103 is Asp, orSer; Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln,Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Phe, Ser,Trp, Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu,Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys,Asp, Leu, Thr, Ile, Gln, His, Ser, Ala or Pro; Xaa at position 109 isArg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys,Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser, Ala, or Trp; Xaa atposition Ill is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr,Val, Gln, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser,Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu,Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 isLys; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa atposition 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa atposition 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa atposition 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 isGln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa atposition 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from4 to about 44 of the amino acids designated by Xaa are different fromthe corresponding amino acids of native (1-133) human interleukin-3; andwherein from 1 to 14 amino acids are optionally deleted from theN-terminus and/or from 1 to 15 amino acids are optionally deleted fromthe C-terminus of said sequence of SEQ ID NO:1; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor; (ii)removing hematopoietic cells from said patient; (iii) administeringcancer radiation therapy or chemotherapy to said patient; and (iv)returning said hematopoietic cells to said patient.
 16. The method ofclaim 15, wherein in said human interleukin-3 mutant polypeptide, theamino acids which differ from the corresponding residue in native humaninterleukin-3 are selected from the group consisting of:position 17wherein Xaa is Ser, Gly, Asp, or Gln; position 18 wherein Xaa is Asn,His, or Ile; position 23 wherein Xaa is Ile, Ala, Leu, or Gly; position25 wherein Xaa is Thr, His, or Gln; position 26 wherein Xaa is His orAla; position 29 wherein Xaa is Gln or Asn; position 30 wherein Xaa isPro or Gly; position 32 wherein Xaa is Leu, Arg, Asn, or Ala; position34 wherein Xaa is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile, Phe, Thr, orMet; position 35 wherein Xaa is Leu, Ala, Asn, or Pro; position 38wherein Xaa is Asn or Ala; position 42 wherein Xaa is Gly, Asp, Ser,Ala, Asn, Ile, Leu, Met, Tyr or Arg; position 45 wherein Xaa is Gln,Val, Met, Leu, Ala, Asn, Glu, or Lys; position 46 wherein Xaa is Asp,Phe, Ser, Gln, Glu, His, Val or Thr; position 50 wherein Xaa is Glu,Asn, Ser or Asp; position 51 wherein Xaa is Asn, Arg, Pro, Thr, or His;position 55 wherein Xaa is Arg, Leu, or Gly; position 56 wherein Xaa isPro, Gly, Ser, Ala, Asn, Val, Leu or Gln; position 62 wherein Xaa isAsn, Pro, or Thr; position 64 wherein Xaa is Ala or Asn; position 65wherein Xaa is Val or Thr; position 67 wherein Xaa is Ser or Phe;position 68 wherein Xaa is Leu or Phe; position 69 wherein Xaa is Gln,Ala, Glu, or Arg; position 76 wherein Xaa is Ser, Val, Asn, Pro, or Gly;position 77 wherein Xaa is Ile or Leu; position 79 wherein Xaa is Lys,Asn, Met, Arg, Ile, or Gly; position 80 wherein Xaa is Asn, Gly, Glu, orArg; position 82 wherein Xaa is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His,Met, Phe, Ser, Thr, Tyr or Val; position 87 wherein Xaa is Leu or Ser;position 88 wherein Xaa is Ala or Trp; position 91 wherein Xaa is Ala orPro; position 93 wherein Xaa is Thr, Asp, or Ala; position 95 whereinXaa is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; position 98 wherein Xaais His, Ile, Asn, Ala, Thr, Gln, Glu, Lys, Met, Ser, Tyr, Val or Leu;position 99 wherein Xaa is Ile or Leu; position 100 wherein Xaa is Lysor Arg; position 101 wherein Xaa is Asp; position 105 wherein Xaa isAsn, Pro, Ser, Ile or Asp; position 108 wherein Xaa is Arg, Ala, or Ser;position 109 wherein Xaa is Arg, Thr, Glu, Leu, or Ser; position 112wherein Xaa is Thr or Gln; position 116 wherein Xaa is Lys; position 120wherein Xaa is Asn, Pro, Leu, His, Val, or Gln; position 121 wherein Xaais Ala, Ser, Ile, Pro, or Asp; position 122 wherein Xaa is Gln, Met,Trp, Phe, Pro, His, Ile, or Tyr; position 123 wherein Xaa is Ala, Met,Glu, Ser, or Leu.
 17. The method of claim 15, wherein in said humaninterleukin-3 mutant polypeptide, the amino acids which differ from thecorresponding residue in native human interleukin-3 are selected fromthe group consisting of:position 42 wherein Xaa is Gly, Asp, Ser, Ile,Leu, Met, Tyr, or Ala; position 45 wherein Xaa is Gln, Val, Met or Asn;position 46 wherein Xaa is Asp, Ser, Gln, His or Val; position 50wherein Xaa is Glu or Asp; position 51 wherein Xaa is Asn, Pro or Thr;position 62 wherein Xaa is Asn or Pro; position 76 wherein Xaa is Ser,or Pro; position 82 wherein Xaa is Leu, Trp, Asp, Asn Glu, His, Phe, Seror Tyr; position 95 wherein Xaa is His, Arg, Thr, Asn or Ser; position98 wherein Xaa is His, Ile, Leu, Ala, Gln, Lys, Met, Ser, Tyr or Val;position 100 wherein Xaa is Lys or Arg; position 105 wherein Xaa is Asn,or Pro; position 108 wherein Xaa is Arg, Ala, or Ser; position 121wherein Xaa is Ala, or Ile; position 122 wherein Xaa is Gln, or Ile; andposition 123 wherein Xaa is Ala, Met or Glu.
 18. A method of treating apatient comprising the steps of:(i) administering to said patient, anamount effective to promote the proliferation and/or differentiation ofhematopoietic cells in said patient of a composition comprising;a humaninterleukin-3 variant polypeptide selected from the group consistingof:(a) a sequence of SEQ ID NO:4; and (b) a polypeptide comprising anN-terminal methionine residue, alanine residue or methionine-alaninedi-peptide immediately preceding said sequence according to (a);wherein;Xaa at position 3 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaaat position 4 is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 5is Met, Phe, Ile, Arg, Gly, Ala, or Cys; Xaa at position 6 is Ile, Cys,Gln, Glu, Arg, Pro, or Ala; Xaa at position 7 is Asp, Phe, Lys, Arg,Ala, Gly, Glu, Gln, Asn, Thr, Ser or Val; Xaa at position 8 is Glu, Trp,Pro, Ser, Ala, His, Asp, Asn, Gln, Leu, Val, or Gly; Xaa at position 9is Ile, Val, Ala, Leu, Gly, Trp, Lys, Phe, Ser, or Arg; Xaa at position10 is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 11 is Thr,His, Gly, Gln, Arg, Pro, or Ala; Xaa at position 12 is His, Thr, Phe,Gly, Arg, Ala, or Trp; Xaa at position 13 is Leu, Gly, Arg, Thr, Ser, orAla; Xaa at position 14 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaaat position 15 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 16 isPro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys; Xaa at position 17 isPro, Asp, Gly, Ala, Arg, Leu, or Gln; Xaa at position 18 is Leu, Val,Arg, Gln, Asn, Gly, Ala, or Glu; Xaa at position 19 is Pro, Leu, Gln,Ala, Thr, or Glu; Xaa at position 20 is Leu, Val, Gly, Ser, Lys, Glu,Gln, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 21 is Leu, Ala,Gly, Asn, Pro, Gln, or Val; Xaa at position 22 is Asp, Leu, or Val; Xaaat position 23 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 24 is Asn,or Ala; Xaa at position 26 is Leu, Trp, or Arg; Xaa at position 27 isAsn, Cys, Arg, Leu, His, Met, Pro; Xaa at position 28 is Gly, Asp, Ser,Cys, Ala, Lys, Asn, Thr, Leu, Val, Glu, Phe, Tyr, Ile or Met; Xaa atposition 29 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr,Gly or Ser; Xaa at position 30 is Asp, Ser, Leu, Arg, Lys, Thr, Met,Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 31 is Gln, Pro, Phe,Val, Met, Leu, Thr, Lys, Asp, Asn, Arg, Ser, Ala, Ile, Glu, His or Trp;Xaa at position 32 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly; Xaa at position 33 is Ile, Gly, Val, Ser,Arg, Pro, or His; Xaa at position 34 is Leu, Ser, Cys, Arg, Ile, His,Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 35 is Met,Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 36 is Glu, Leu,Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gln; Xaaat position 37 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position38 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 39 is Leu,Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 40 is Arg,Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His, Ala or Leu; Xaa at position41 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 42 is Pro, Gly,Cys, Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaaat position 43 is Asn or Gly; Xaa at position 44 is Leu, Ser, Asp, Arg,Gln, Val, or Cys; Xaa at position 45 is Glu, Tyr, His, Leu, Pro, or Arg;Xaa at position 46 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position47 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 48 is Asn,His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 49 is Arg, Tyr,Trp, Lys, Ser, His, Pro, or Val; Xaa at position 50 is Ala, Asn, Pro,Ser, or Lys; Xaa at position 51 is Val, Thr, Pro, His, Leu, Phe, or Ser;Xaa at position 52 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa atposition 53 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa atposition 54 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa atposition 55 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa atposition 56 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 57 isAla, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 58is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 59 is Ala,Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 60 is Ile, Met,Thr, Pro, Arg, Gly, Ala; Xaa at position 61 is Glu, Lys, Gly, Asp, Pro,Trp, Arg, Ser, Gln, or Leu; Xaa at position 62 is Ser, Val, Ala, Asn,Trp, Glu, Pro, Gly, or Asp; Xaa at position 63 is Ile, Ser, Arg, Thr, orLeu; Xaa at position 64 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa atposition 65 is Lys, Thr, Gly, Asn, Met, Arg, Ile, or Asp; Xaa atposition 66 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa atposition 67 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa atposition 68 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser,Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 69 is Pro, Ala, Thr,Trp, Arg, or Met; Xaa at position 70 is Cys, Glu, Gly, Arg, Met, or Val;Xaa at position 71 is Leu, Asn, Val, or Gln; Xaa at position 72 is Pro,Cys, Arg, Ala, or Lys; Xaa at position 73 is Leu, Ser, Trp, or Gly; Xaaat position 74 is Ala, Lys, Arg, Val, or Trp; Xaa at position 75 is Thr,Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 76 is Ala,Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 77 is Ala, Pro,Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 78 is Pro, Phe, Arg,Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 79 is Thr, Asp,Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 80 is Arg, Ile, Ser,Glu, Leu, Val, Gln, Lys, His, Ala or Pro; Xaa at position 81 is His,Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile orTyr; Xaa at position 82 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa atposition 83 is Ile, Val, Lys, Ala, or Asn; Xaa at position 84 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 85 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 86 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, Pro; Xaa at position 87 is Asp; Xaa at position 88 isGly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 89 is Asp, or Ser;Xaa at position 90 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly; Xaa at position 91 is Asn, Pro, Ala, Phe, Ser, Trp,Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 92 is Glu, Ser,Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 94 is Arg, Lys, Asp,Leu, Thr, Ile, Gln, His, Ser, Ala, or Pro; Xaa at position 95 is Arg,Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 96 is Lys, Asn,Thr, Leu, Gln, Arg, His, Glu, Ser, Ala or Trp; Xaa at position 97 isLeu, Ile, Arg, Asp, or Met; Xaa at position 98 is Thr, Val, Gln, Tyr,Glu, His, Ser, or Phe; Xaa at position 99 is Phe, Ser, Cys, His, Gly,Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 100 is Tyr,Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 101 is Leu, Asn, Val,Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 102 is Lys; Xaa atposition 103 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position104 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 105 isGlu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 106 is Asn,Ala, Pro, Leu, His, Val, or Gln; Xaa at position 107 is Ala, Ser, Ile,Asn, Pro, Lys, Asp, or Gly; Xaa at position 108 is Gln, Ser, Met, Trp,Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 109 is Ala, Met,Glu, His, Ser, Pro, Tyr, or Leu; wherein from 4 to about 44 of the aminoacids designated by Xaa are different from the corresponding nativeamino acids of (1-133) human interleukin-3; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor; (ii)removing hematopoietic cells from said patient; (iii) administeringcancer radiation therapy of chemotherapy to said patient; and (iv)returning said hematopoietic cells to said patient.
 19. The method ofclaim 18, wherein the sequence of said human interleukin-3 variantpolypeptide is selected from the group consisting of:SEQ ID NO:9, SEQ IDNO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ IDNO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ IDNO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ IDNO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ IDNO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ IDNO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ IDNO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ IDNO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, and SEQ ID NO:49. 20.The method of claim 18, wherein in said human interleukin-3 mutantpolypeptide, the amino acids which differ from the corresponding residuein native human interleukin-3 are selected from the group consistingof:position 3 wherein Xaa is Ser, Gly, Asp, or Gln; position 4 whereinXaa is Asn, His, or Ile; position 9 wherein Xaa is Ile, Ala, Leu, orGly; position 11 wherein Xaa is Thr, His, or Gln; position 12 whereinXaa is His or Ala; position 15 wherein Xaa is Gln or Asn; position 16wherein Xaa is Pro or Gly; position 18 wherein Xaa is Leu, Arg, Asn, orAla; position 20 wherein Xaa is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile,Phe, Thr or Met; position 21 wherein Xaa is Leu, Ala, Asn, or Pro;position 24 wherein Xaa is Asn or Ala; position 28 wherein Xaa is Gly,Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr or Arg; position 31 wherein Xaais Gln, Val, Met, Leu, Ala, Asn, Glu or Lys; position 32 wherein Xaa isAsp, Phe, Ser, Ala, Gln, Glu, His, Val or Thr; position 36 wherein Xaais Glu, Asn, Ser or Asp; position 37 wherein Xaa is Asn, Arg, Pro, Thr,or His; position 41 wherein Xaa is Arg, Leu, or Gly; position 42 whereinXaa is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln; position 48 wherein Xaais Asn, Pro, or Thr; position 50 wherein Xaa is Ala or Asn; position 51wherein Xaa is Val or Thr; position 53 wherein Xaa is Ser or Phe;position 54 wherein Xaa is Leu or Phe; position 55 wherein Xaa is Gln,Ala, Glu, or Arg; position 62 wherein Xaa is Ser, Val, Asn, Pro, or Gly;position 63 wherein Xaa is Ile or Leu; position 65 wherein Xaa is Lys,Asn, Met, Arg, Ile, or Gly; position 66 wherein Xaa is Asn, Gly, Glu, orArg; position 68 wherein Xaa is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His,Met, Phe, Ser, Thr, Tyr or Val; position 73 wherein Xaa is Leu or Ser;position 74 wherein Xaa is Ala or Trp; position 77 wherein Xaa is Ala orPro; position 79 wherein Xaa is Thr, Asp, or Ala; position 81 whereinXaa is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; position 84 wherein Xaais His, Ile, Asn, Ala, Thr, Arg, Gln, Glu, Lys, Met, Ser, Tyr, Val orLeu; position 85 wherein Xaa is Ile or Leu; position 86 wherein Xaa isLys or Arg; position 87 wherein Xaa is Asp; position 91 wherein Xaa isAsn, Pro, Ser, Ile or Asp; position 94 wherein Xaa is Arg, Ala, or Ser;position 95 wherein Xaa is Arg, Thr, Glu, Leu, or Ser; position 98wherein Xaa is Thr or Gln; position 102 wherein Xaa is Lys; position 103wherein Xaa is Thr, Ala, His, Phe, Tyr or Ser; position 106 wherein Xaais Asn, Pro, Leu, His, Val, or Gln; position 107 wherein Xaa is Ala,Ser, Ile, Pro, or Asp; position 108 wherein Xaa is Gln, Met, Trp, Phe,Pro, His, Ile, or Tyr; and position 109 wherein Xaa is Ala, Met, Glu,Ser, or Leu.
 21. A method of treating a patient comprising the stepsof:(i) administering to said patient, an amount effective to promote theproliferation and/or differentiation of hematopoietic cells in saidpatient of a composition comprising;a human interleukin-3 variantpolypeptide selected from the group consisting of:(a) a sequence of SEQID NO:8; and (b) a polypeptide comprising an N-terminal residue, alanineresidue or methionine-alanine di-peptide immediately preceding saidsequence according to (a); wherein;Xaa at position 4 is Asn or Ile; Xaaat position 5 is Met, Ala or Ile; Xaa at position 6 is Ile, Pro or Leu;Xaa at position 9 is Ile, Ala or Leu; Xaa at position 11 is Thr or His;Xaa at position 15 is Gln, Arg, Val or Leu; Xaa at position 18 is Leu,Ala, Asn or Arg; Xaa at position 20 is Leu or Ser; Xaa at position 23 isPhe, Pro, or Ser; Xaa at position 24 is Asn or Ala; Xaa at position 28is Gly, Ala, Ser, Asp or Asn; Xaa at position 31 is Gln, Val, or Met;Xaa at position 32 is Asp or Ser; Xaa at position 35 is Met, Ile, Leu orAsp; Xaa at position 36 is Glu or Asp; Xaa at position 37 is Asn, Arg orSer; Xaa at position 41 is Arg, Leu, or Thr; Xaa at position 42 is Proor Ser; Xaa at position 45 is Glu or Leu; Xaa at position 46 is Ala orSer; Xaa at position 48 is Asn, Val or Pro; Xaa at position 49 is Arg orHis; Xaa at position 51 is Val or Ser; Xaa at position 53 is Ser, Asn,His or Gly; Xaa at position 55 is Gln or Glu; Xaa at position 59 is Alaor Gly; Xaa at position 62 is Ser, Ala or Pro; Xaa at position 65 isLys, Arg or Ser; Xaa at position 67 is Leu, Glu, or Val; Xaa at position68 is Leu, Glu, Val or Trp; Xaa at position 71 is Leu or Val; Xaa atposition 73 is Leu, Ser or Trp; Xaa at position 74 is Ala or Trp; Xaa atposition 77 is Ala or Pro; Xaa at position 79 is Pro or Ser; Xaa atposition 81 is His or Thr; Xaa at position 84 is His, Ile, or Thr; Xaaat position 86 is Lys or Arg; Xaa at position 87 is Asp; Xaa at position91 is Asn or Gln; Xaa at position 95 is Arg, Glu, Leu; Xaa at position98 is Thr or Gln; Xaa at position 102 is Lys; Xaa at position 103 is Thror Ser; Xaa at position 106 is Asn, Gln, or His; Xaa at position 109 isAla or Glu; wherein from 4 to about 44 of the amino acids designated byXaa are different from the corresponding amino acids of native (1-133)human interleukin-3; and wherein said human interleukin-3 variantpolypeptide has at least three times greater activity, relative tonative human interleukin-3, in at least one assay selected from thegroup consisting of: AML cell proliferation, TF-1 cell proliferation andMethylcellulose assay; and a factor selected from the group consistingof: a colony stimulating factor, a cytokine, a lymphokine, aninterleukin, and a hematopoietic growth factor; (ii) removinghematopoietic cells from said patient; (iii) administering cancerradiation therapy or chemotherapy to said patient; and (iv) returningsaid hematopoietic cells to said patient.
 22. The method of claim 14,15, 16, 17, 18, 19, 20 or 21 wherein said factor is selected from thegroup consisting of; GM-CSF, CSF-1, G-CSF, G-CSF (Ser¹⁷), M-CSF,erythropoietin (EPO), c-mpl ligand, IL-1, IL-4, IL-2, IL-5, IL-6, IL-7,IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 ligand, human growthhormone, B-cell growth factor, B-cell differentiation factor, eosinophildifferentiation factor and stem cell factor (SCF).
 23. A method oftreating a patient having a side effect of cancer chemotherapy orradiation therapy comprising; administering to said patient atherapeutically effective amount of a composition comprising;a modifiedhuman interleukin-3 (hIL-3) amino acid sequence, wherein said modifiedsequence differs from the sequence of native (1-133) hIL-3 by thereplacement of from 4 to about 44 of the residues corresponding topositions 17-123 of native (1-133) hIL-3 by other amino acids, with theproviso that the residues corresponding to positions 101 and 116 are notAla or Val, respectively; wherein said modified sequence optionallyfurther differs from the sequence of native (1-133) hIL-3 by thedeletion of from 1 to 14 residues from the N-terminus of native (1-133)hIL-3, the deletion of from 1 to 15 residues from the C-terminus ofnative (1-133) hIL-3, or both; and wherein said modified interleukin-3(hIL-3) amino acid sequence has at least three times greater activity,relative to native human interleukin-3, in at least one assay selectedfrom the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine alymphokine, an interleukin and a hematopoietic growth factor.
 24. Amethod of treating a patient having a side effect of cancer chemotherapyor radiation therapy comprising; administering to said patient atherapeutically effective amount of a composition comprising;a humaninterleukin-3 variant polypeptide selected from the group consistingof:(a) a sequence of SEQ ID NO:1; and (b) a polypeptide comprising anN-terminal residue, alanine residue or methionine-alanine di-peptideimmediately preceding said sequence according to (a); wherein;Xaa atposition 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg; Xaa at position 18is Asn, His, Leu, Ile, Phe, Arg, or Gln; Xaa at position 19 is Met, Phe,Ile, Arg, Gly, Ala, or Cys; Xaa at position 20 is Ile, Cys, Gln, Glu,Arg, Pro, or Ala; Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly,Glu, Gln, Asn, Thr, Ser or Val; Xaa at position 22 is Glu, Trp, Pro,Ser, Ala, His, Asp, Asn, Gln, Leu, Val or Gly; Xaa at position 23 isIle, Val, Ala, Leu, Gly, Trp, Lys, Phe, Ser, or Arg; Xaa at position 24is Ile, Gly, Val, Arg, Ser, Phe, or Leu; Xaa at position 25 is Thr, His,Gly, Gln, Arg, Pro, or Ala; Xaa at position 26 is His, Thr, Phe, Gly,Arg, Ala, or Trp; Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaa atposition 29 is Gln, Asn, Leu, Pro, Arg, or Val; Xaa at position 30 isPro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys; Xaa at position 31 isPro, Asp, Gly, Ala, Arg, Leu, or Gln; Xaa at position 32 is Leu, Val,Arg, Gln, Asn, Gly, Ala, or Glu; Xaa at position 33 is Pro, Leu, Gln,Ala, Thr, or Glu; Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu,Gln, Thr, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala,Gly, Asn, Pro, Gln, or Val; Xaa at position 36 is Asp, Leu, or Val; Xaaat position 37 is Phe, Ser, Pro, Trp, or Ile; Xaa at position 38 is Asn,or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 isAsn, Cys, Arg, Leu, His, Met, or Pro; Xaa at position 42 is Gly, Asp,Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaaat position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr,Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met,Trp, Glu, Asn, Gln, Ala or Pro; Xaa at position 45 is Gln, Pro, Phe,Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln, Lys, His,Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser,Arg, Pro, or His; Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His,Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met,Arg, Ala, Gly, Pro, Asn, His, or Asp; Xaa at position 50 is Glu, Leu,Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gln; Xaaat position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 53 is Leu,Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met; Xaa at position 54 is Arg,Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys, His, Ala or Leu; Xaa at position55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 56 is Pro, Gly,Cys, Ser, Gln, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaaat position 57 is Asn or Gly; Xaa at position 58 is Leu, Ser, Asp, Arg,Gln, Val, or Cys; Xaa at position 59 is Glu, Tyr, His, Leu, Pro, or Arg;Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr; Xaa at position61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Xaa at position 62 is Asn,His, Val, Arg, Pro, Thr, Asp, or Ile; Xaa at position 63 is Arg, Tyr,Trp, Lys, Ser, His, Pro, or Val; Xaa at position 64 is Ala, Asn, Pro,Ser, or Lys; Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser; Xaa atposition 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His; Xaa atposition 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His; Xaa atposition 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Xaa atposition 70 is Asn, Leu, Val, Trp, Pro, or Ala; Xaa at position 71 isAla, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, or Asn; Xaa at position 72is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp; Xaa at position 73 is Ala,Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa at position 74 is Ile, Met,Thr, Pro, Arg, Gly, Ala; Xaa at position 75 is Glu, Lys, Gly, Asp, Pro,Trp, Arg, Ser, Gln, or Leu; Xaa at position 76 is Ser, Val, Ala, Asn,Trp, Glu, Pro, Gly, or Asp; Xaa at position 77 is Ile, Ser, Arg, Thr, orLeu; Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg; Xaa atposition 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp; Xaa atposition 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg; Xaa atposition 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys; Xaa atposition 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser,Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 83 is Pro, Ala, Thr,Trp, Arg, or Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;Xaa at position 85 is Leu, Asn, Val, or Gln; Xaa at position 86 is Pro,Cys, Arg, Ala, or Lys; Xaa at position 87 is Leu, Ser, Trp, or Gly; Xaaat position 88 is Ala, Lys, Arg, Val, or Trp; Xaa at position 89 is Thr,Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 90 is Ala,Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 91 is Ala, Pro,Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe, Arg,Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr, Asp,Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser,Glu, Leu, Val, Gln, Lys, His, Ala, or Pro; Xaa at position 95 is His,Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, orTyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa atposition 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, or Pro; Xaa at position 101 is Asp; Xaa at position 102is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 103 is Asp, orSer; Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln,Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Phe, Ser,Trp, Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu,Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys,Asp, Leu, Thr, Ile, Gln, His, Ser, Ala or Pro; Xaa at position 109 isArg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys,Ala, Asn, Thr, Leu, Arg, Gln, His, Glu, Ser, Ala, or Trp; Xaa atposition 111 is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr,Val, Gln, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser,Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu,Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 isLys; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa atposition 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa atposition 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa atposition 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 isGln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa atposition 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;wherein from 4to about 44 of the amino acids designated by Xaa are different from thecorresponding amino acids of native (1-133) human interleukin-3; andwherein from 1 to 14 amino acids are optionally deleted from theN-terminus and/or from 1 to 15 amino acids are optionally deleted fromthe C-terminus of said sequence of SEQ ID NO:1; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor.
 25. Themethod of claim 24, wherein in said human interleukin-3 mutantpolypeptide, the amino acids which differ from the corresponding residuein native human interleukin-3 are selected from the group consistingof:position 17 wherein Xaa is Ser, Gly, Asp, or Gln; position 18 whereinXaa is Asn, His, or Ile; position 23 wherein Xaa is Ile, Ala, Leu, orGly; position 25 wherein Xaa is Thr, His, or Gln; position 26 whereinXaa is His or Ala; position 29 wherein Xaa is Gln or Asn; position 30wherein Xaa is Pro or Gly; position 32 wherein Xaa is Leu, Arg, Asn, orAla; position 34 wherein Xaa is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile,Phe, Thr, or Met; position 35 wherein Xaa is Leu, Ala, Asn, or Pro;position 38 wherein Xaa is Asn or Ala; position 42 wherein Xaa is Gly,Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr or Arg; position 45 wherein Xaais Gln, Val, Met, Leu, Ala, Asn, Glu, or Lys; position 46 wherein Xaa isAsp, Phe, Ser, Gln, Glu, His, Val or Thr; position 50 wherein Xaa isGlu, Asn, Ser or Asp; position 51 wherein Xaa is Asn, Arg, Pro, Thr, orHis; position 55 wherein Xaa is Arg, Leu, or Gly; position 56 whereinXaa is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln; position 62 wherein Xaais Asn, Pro, or Thr; position 64 wherein Xaa is Ala or Asn; position 65wherein Xaa is Val or Thr; position 67 wherein Xaa is Ser or Phe;position 68 wherein Xaa is Leu or Phe; position 69 wherein Xaa is Gln,Ala, Glu, or Arg; position 76 wherein Xaa is Ser, Val, Asn, Pro, or Gly;position 77 wherein Xaa is Ile or Leu; position 79 wherein Xaa is Lys,Asn, Met, Arg, Ile, or Gly; position 80 wherein Xaa is Asn, Gly, Glu, orArg; position 82 wherein Xaa is Leu, Gln, Trp, Arg, Asp, Asn, Glu, His,Met, Phe, Ser, Thr, Tyr or Val; position 87 wherein Xaa is Leu or Ser;position 88 wherein Xaa is Ala or Trp; position 91 wherein Xaa is Ala orPro; position 93 wherein Xaa is Thr, Asp, or Ala; position 95 whereinXaa is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; position 98 wherein Xaais His, Ile, Asn, Ala, Thr, Gln, Glu, Lys, Met, Ser, Tyr, Val or Leu;position 99 wherein Xaa is Ile or Leu; position 100 wherein Xaa is Lysor Arg; position 101 wherein Xaa is Asp; position 105 wherein Xaa isAsn, Pro, Ser, Ile or Asp; position 108 wherein Xaa is Arg, Ala, or Ser;position 109 wherein Xaa is Arg, Thr, Glu, Leu, or Ser; position 112wherein Xaa is Thr or Gln; position 116 wherein Xaa is Lys; position 120wherein Xaa is Asn, Pro, Leu, His, Val, or Gln; position 121 wherein Xaais Ala, Ser, Ile, Pro, or Asp; position 122 wherein Xaa is Gln, Met,Trp, Phe, Pro, His, Ile, or Tyr; and position 123 wherein Xaa is Ala,Met, Glu, Ser, or Leu.
 26. The method of claim 24, wherein in said humaninterleukin-3 mutant polypeptide, the amino acids which differ from thecorresponding residue in native human interleukin-3 are selected fromthe group consisting of:position 42 wherein Xaa is Gly, Asp, Ser, Ile,Leu, Met, Tyr, or Ala; position 45 wherein Xaa is Gln, Val, Met or Asn;position 46 wherein Xaa is Asp, Ser, Gln, His or Val; position 50wherein Xaa is Glu or Asp; position 51 wherein Xaa is Asn, Pro or Thr;position 62 wherein Xaa is Asn or Pro; position 76 wherein Xaa is Ser,or Pro; position 82 wherein Xaa is Leu, Trp, Asp, Asn Glu, His, Phe, Seror Tyr; position 95 wherein Xaa is His, Arg, Thr, Asn or Ser; position98 wherein Xaa is His, Ile, Leu, Ala, Gln, Lys, Met, Ser, Tyr or Val;position 100 wherein Xaa is Lys or Arg; position 105 wherein Xaa is Asn,or Pro; position 108 wherein Xaa is Arg, Ala, or Ser; position 121wherein Xaa is Ala, or Ile; position 122 wherein Xaa is Gln, or Ile; andposition 123 wherein Xaa is Ala, Met or Glu.
 27. A method of treating apatient having a side effect of cancer chemotherapy or radiation therapycomprising administering to said patient a therapeutically effectiveamount of a composition comprising;a human interleukin-3 variantpolypeptide selected from the group consisting of:(a) a sequence of SEQID NO:4; and (b) a polypeptide comprising an N-terminal residue, alanineresidue or methionine-alanine di-peptide immediately preceding saidsequence according to (a); wherein;Xaa at position 3 is Ser, Lys, Gly,Asp, Met, Gln, or Arg; Xaa at position 4 is Asn, His, Leu, Ile, Phe,Arg, or Gln; Xaa at position 5 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;Xaa at position 6 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala; Xaa atposition 7 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser orVal; Xaa at position 8 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,Leu, Val, or Gly; Xaa at position 9 is Ile, Val, Ala, Leu, Gly, Trp,Lys, Phe, Ser, or Arg; Xaa at position 10 is Ile, Gly, Val, Arg, Ser,Phe, or Leu; Xaa at position 11 is Thr, His, Gly, Gln, Arg, Pro, or Ala;Xaa at position 12 is His, Thr, Phe, Gly, Arg, Ala, or Trp; Xaa atposition 13 is Leu, Gly, Arg, Thr, Ser, or Ala; Xaa at position 14 isLys, Arg, Leu, Gln, Gly, Pro, Val or Trp; Xaa at position 15 is Gln,Asn, Leu, Pro, Arg, or Val; Xaa at position 16 is Pro, His, Thr, Gly,Asp, Gln, Ser, Leu, or Lys; Xaa at position 17 is Pro, Asp, Gly, Ala,Arg, Leu, or Gln; Xaa at position 18 is Leu, Val, Arg, Gln, Asn, Gly,Ala, or Glu; Xaa at position 19 is Pro, Leu, Gln, Ala, Thr, or Glu; Xaaat position 20 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr, Arg, Ala, Phe,Ile or Met; Xaa at position 21 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;Xaa at position 22 is Asp, Leu, or Val; Xaa at position 23 is Phe, Ser,Pro, Trp, or Ile; Xaa at position 24 is Asn, or Ala; Xaa at position 26is Leu, Trp, or Arg; Xaa at position 27 is Asn, Cys, Arg, Leu, His, Met,Pro; Xaa at position 28 is Gly, Asp, Ser, Cys, Ala, Lys, Asn, Thr, Leu,Val, Glu, Phe, Tyr, Ile or Met; Xaa at position 29 is Glu, Asn, Tyr,Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr, Gly or Ser; Xaa at position 30is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gln, Ala or Pro;Xaa at position 31 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys, Asp, Asn,Arg, Ser, Ala, Ile, Glu, His or Trp; Xaa at position 32 is Asp, Phe,Ser, Thr, Cys, Glu, Asn, Gln, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaaat position 33 is Ile, Gly, Val, Ser, Arg, Pro, or His; Xaa at position34 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met, Val orAsn; Xaa at position 35 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;Xaa at position 36 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile,Val, His, Phe, Met or Gln; Xaa at position 37 is Asn, Arg, Met, Pro,Ser, Thr, or His; Xaa at position 38 is Asn, His, Arg, Leu, Gly, Ser, orThr; Xaa at position 39 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, orMet; Xaa at position 40 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn, Lys,His, Ala or Leu; Xaa at position 41 is Arg, Thr, Val, Ser, Leu, or Gly;Xaa at position 42 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His, Thr, Ala,Tyr, Phe, Leu, Val or Lys; Xaa at position 43 is Asn or Gly; Xaa atposition 44 is Leu, Ser, Asp, Arg, Gln, Val, or Cys; Xaa at position 45is Glu, Tyr, His, Leu, Pro, or Arg; Xaa at position 46 is Ala, Ser, Pro,Tyr, Asn, or Thr; Xaa at position 47 is Phe, Asn, Glu, Pro, Lys, Arg, orSer; Xaa at position 48 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;Xaa at position 49 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val; Xaa atposition 50 is Ala, Asn, Pro, Ser, or Lys; Xaa at position 51 is Val,Thr, Pro, His, Leu, Phe, or Ser; Xaa at position 52 is Lys, Ile, Arg,Val, Asn, Glu, or Ser; Xaa at position 53 is Ser, Ala, Phe, Val, Gly,Asn, Ile, Pro, or His; Xaa at position 54 is Leu, Val, Trp, Ser, Ile,Phe, Thr, or His; Xaa at position 55 is Gln, Ala, Pro, Thr, Glu, Arg,Trp, Gly, or Leu; Xaa at position 56 is Asn, Leu, Val, Trp, Pro, or Ala;Xaa at position 57 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln, Trp, orAsn; Xaa at position 58 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;Xaa at position 59 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg; Xaa atposition 60 is Ile, Met, Thr, Pro, Arg, Gly, Ala; Xaa at position 61 isGlu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gln, or Leu; Xaa at position 62is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp; Xaa at position 63 isIle, Ser, Arg, Thr, or Leu; Xaa at position 64 is Leu, Ala, Ser, Glu,Phe, Gly, or Arg; Xaa at position 65 is Lys, Thr, Gly, Asn, Met, Arg,Ile, or Asp; Xaa at position 66 is Asn, Trp, Val, Gly, Thr, Leu, Glu, orArg; Xaa at position 67 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;Xaa at position 68 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr,Ser, Ala, Tyr, Phe, Ile, Met or Val; Xaa at position 69 is Pro, Ala,Thr, Trp, Arg, or Met; Xaa at position 70 is Cys, Glu, Gly, Arg, Met, orVal; Xaa at position 71 is Leu, Asn, Val, or Gln; Xaa at position 72 isPro, Cys, Arg, Ala, or Lys; Xaa at position 73 is Leu, Ser, Trp, or Gly;Xaa at position 74 is Ala, Lys, Arg, Val, or Trp; Xaa at position 75 isThr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser; Xaa at position 76 isAla, Pro, Ser, Thr, Gly, Asp, Ile, or Met; Xaa at position 77 is Ala,Pro, Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 78 is Pro, Phe,Arg, Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 79 is Thr,Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 80 is Arg, Ile,Ser, Glu, Leu, Val, Gln, Lys, His, Ala or Pro; Xaa at position 81 isHis, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe,Ile or Tyr; Xaa at position 82 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaaat position 83 is Ile, Val, Lys, Ala, or Asn; Xaa at position 84 is His,Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gln, Ser, Phe, Met, Val, Lys, Arg,Tyr or Pro; Xaa at position 85 is Ile, Leu, Arg, Asp, Val, Pro, Gln,Gly, Ser, Phe, or His; Xaa at position 86 is Lys, Tyr, Leu, His, Arg,Ile, Ser, Gln, Pro; Xaa at position 87 is Asp; Xaa at position 88 isGly, Leu, Glu, Lys, Ser, Tyr, or Pro; Xaa at position 89 is Asp, or Ser;Xaa at position 90 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gln, Lys,Ala, Phe, or Gly; Xaa at position 91 is Asn, Pro, Ala, Phe, Ser, Trp,Gln, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 92 is Glu, Ser,Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 94 is Arg, Lys, Asp,Leu, Thr, Ile, Gln, His, Ser, Ala, or Pro; Xaa at position 95 is Arg,Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 96 is Lys, Asn,Thr, Leu, Gln, Arg, His, Glu, Ser, Ala or Trp; Xaa at position 97 isLeu, Ile, Arg, Asp, or Met; Xaa at position 98 is Thr, Val, Gln, Tyr,Glu, His, Ser, or Phe; Xaa at position 99 is Phe, Ser, Cys, His, Gly,Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 100 is Tyr,Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 101 is Leu, Asn, Val,Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 102 is Lys; Xaa atposition 103 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position104 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 105 isGlu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 106 is Asn,Ala, Pro, Leu, His, Val, or Gln; Xaa at position 107 is Ala, Ser, Ile,Asn, Pro, Lys, Asp, or Gly; Xaa at position 108 is Gln, Ser, Met, Trp,Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 109 is Ala, Met,Glu, His, Ser, Pro, Tyr, or Leu;wherein from 4 to about 44 of the aminoacids designated by Xaa are different from the corresponding nativeamino acids of (1-133) human interleukin-3; and wherein said humaninterleukin-3 variant polypeptide has at least three times greateractivity, relative to native human interleukin-3, in at least one assayselected from the group consisting of: AML cell proliferation, TF-1 cellproliferation and Methylcellulose assay; and a factor selected from thegroup consisting of: a colony stimulating factor, a cytokine, alymphokine, an interleukin, and a hematopoietic growth factor.
 28. Themethod of claim 27, wherein the sequence of said human interleukin-3variant polypeptide is selected from the group consisting of:SEQ IDNO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ IDNO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ IDNO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ IDNO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ IDNO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ IDNO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ IDNO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ IDNO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, and SEQID NO:49.
 29. The method of claim 27, wherein in said humaninterleukin-3 mutant polypeptide, the amino acids which differ from thecorresponding residue in native human interleukin-3 are selected fromthe group consisting of:Xaa at position 3 is Ser, Gly, Asp, or Gln; Xaaat position 4 is Asn, His, or Ile; Xaa at position 9 is Ile, Ala, Leu,or Gly; Xaa at position 11 is Thr, His, or Gln; Xaa at position 12 isHis or Ala; Xaa at position 15 is Gln or Asn; Xaa at position 16 is Proor Gly; Xaa at position 18 is Leu, Arg, Asn, or Ala; Xaa at position 20is Leu, Val, Ser, Ala, Arg, Gln, Glu, Ile, Phe, Thr or Met; Xaa atposition 21 is Leu, Ala, Asn, or Pro; Xaa at position 24 is Asn or Ala;Xaa at position 28 is Gly, Asp, Ser, Ala, Asn, Ile, Leu, Met, Tyr orArg; Xaa at position 31 is Gln, Val, Met, Leu, Ala, Asn, Glu or Lys; Xaaat position 32 is Asp, Phe, Ser, Ala, Gln, Glu, His, Val or Thr; Xaa atposition 36 is Glu, Asn, Ser or Asp; Xaa at position 37 is Asn, Arg,Pro, Thr, or His; Xaa at position 41 is Arg, Leu, or Gly; Xaa atposition 42 is Pro, Gly, Ser, Ala, Asn, Val, Leu or Gln; Xaa at position48 is Asn, Pro, or Thr; Xaa at position 50 is Ala or Asn; Xaa atposition 51 is Val or Thr; Xaa at position 53 is Ser or Phe; Xaa atposition 54 is Leu or Phe; Xaa at position 55 is Gln, Ala, Glu, or Arg;Xaa at position 62 is Ser, Val, Asn, Pro, or Gly; Xaa at position 63 isIle or Leu; Xaa at position 65 is Lys, Asn, Met, Arg, Ile, or Gly; Xaaat position 66 is Asn, Gly, Glu, or Arg; Xaa at position 68 is Leu, Gln,Trp, Arg, Asp, Asn, Glu, His, Met, Phe, Ser, Thr, Tyr or Val; Xaa atposition 73 is Leu or Ser; Xaa at position 74 is Ala or Trp; Xaa atposition 77 is Ala or Pro; Xaa at position 79 is Thr, Asp, or Ala; Xaaat position 81 is His, Pro, Arg, Val, Gly, Asn, Ser or Thr; Xaa atposition 84 is His, Ile, Asn, Ala, Thr, Arg, Gln, Glu, Lys, Met, Ser,Tyr, Val or Leu; Xaa at position 85 is Ile or Leu; Xaa at position 86 isLys or Arg; Xaa at position 87 is Asp; Xaa at position 91 is Asn, Pro,Ser, Ile or Asp; Xaa at position 94 is Arg, Ala, or Ser; Xaa at position95 is Arg, Thr, Glu, Leu, or Ser; Xaa at position 98 is Thr or Gln; Xaaat position 102 is Lys; Xaa at position 103 is Thr, Ala, His, Phe, Tyror Ser; Xaa at position 106 is Asn, Pro, Leu, His, Val, or Gln; Xaa atposition 107 is Ala, Ser, Ile, Pro, or Asp; Xaa at position 108 is Gln,Met, Trp, Phe, Pro, His, Ile, or Tyr; and Xaa at position 109 is Ala,Met, Glu, Ser, or Leu.
 30. A method of treating a patient having a sideeffect of cancer chemotherapy or radiation therapy comprising;administering to said patient a therapeutically effective amount of acomposition comprising;a human interleukin-3 variant polypeptideselected from the group consisting of:(a) a sequence of SEQ ID NO:8; and(b) a polypeptide comprising an N-terminal residue, alanine residue ormethionine-alanine di-peptide immediately preceding said sequenceaccording to (a); wherein;Xaa at position 4 is Asn or Ile; Xaa atposition 5 is Met, Ala or Ile; Xaa at position 6 is Ile, Pro or Leu; Xaaat position 9 is Ile, Ala or Leu; Xaa at position 11 is Thr or His; Xaaat position 15 is Gln, Arg, Val or Leu; Xaa at position 18 is Leu, Ala,Asn or Arg; Xaa at position 20 is Leu or Ser; Xaa at position 23 is Phe,Pro, or Ser; Xaa at position 24 is Asn or Ala; Xaa at position 28 isGly, Ala, Ser, Asp or Asn; Xaa at position 31 is Gln, Val, or Met; Xaaat position 32 is Asp or Ser; Xaa at position 35 is Met, Ile, Leu orAsp; Xaa at position 36 is Glu or Asp; Xaa at position 37 is Asn, Arg orSer; Xaa at position 41 is Arg, Leu, or Thr; Xaa at position 42 is Proor Ser; Xaa at position 45 is Glu or Leu; Xaa at position 46 is Ala orSer; Xaa at position 48 is Asn, Val or Pro; Xaa at position 49 is Arg orHis; Xaa at position 51 is Val or Ser; Xaa at position 53 is Ser, Asn,His or Gly; Xaa at position 55 is Gln or Glu; Xaa at position 59 is Alaor Gly; Xaa at position 62 is Ser, Ala or Pro; Xaa at position 65 isLys, Arg or Ser; Xaa at position 67 is Leu, Glu, or Val; Xaa at position68 is Leu, Glu, Val or Trp; Xaa at position 71 is Leu or Val; Xaa atposition 73 is Leu, Ser or Trp; Xaa at position 74 is Ala or Trp; Xaa atposition 77 is Ala or Pro; Xaa at position 79 is Pro or Ser; Xaa atposition 81 is His or Thr; Xaa at position 84 is His, Ile, or Thr; Xaaat position 86 is Lys or Arg; Xaa at position 87 is Asp; Xaa at position91 is Asn or Gln; Xaa at position 95 is Arg, Glu, Leu; Xaa at position98 is Thr or Gln; Xaa at position 102 is Lys; Xaa at position 103 is Thror Ser; Xaa at position 106 is Asn, Gln, or His; Xaa at position 109 isAla or Glu;wherein from 4 to about 44 of the amino acids designated byXaa are different from the corresponding amino acids of native (1-133)human interleukin-3; and wherein said human interleukin-3 variantpolypeptide has at least three times greater activity, relative tonative human interleukin-3, in at least one assay selected from thegroup consisting of: AML cell proliferation, TF-1 cell proliferation andMethylcellulose assay; and a factor selected from the group consistingof: a colony stimulating factor, a cytokine, a lymphokine, aninterleukin, and a hematopoietic growth factor.
 31. The method of claim23, 24, 25, 26, 27, 28, 29, or 30 wherein said factor is selected fromthe group consisting of; GM-CSF, CSF-1, G-CSF, G-CSF (Ser¹⁷), M-CSF,erythropoietin (EPO), c-mpl ligand, IL-1, IL-4, IL-2, IL-5, IL-6, IL-7,IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 ligand, human growthhormone, B-cell growth factor, B-cell differentiation factor, eosinophildifferentiation factor and stem cell factor (SCF).